This is such a well-worn route it's hardly worth mentioning, but then again I'm surprised at the number of travelers who take it direct without considering all the lifetime experiences they pass up before they get to Cusco.
For hikers of any ability, the town of Chivay should be your first point of order, because from here you can head out to the unforgettable Colca Canyon, one of the deepest canyons in the world. You don't have to go down to appreciate its splendor. On the way there you'll skirt the Aguada Blanca National Reserve, inhabited by herds of vicuñas and alpacas. One of the best hikes is at the top of the steepest side of Colca Canyon where you come to Condor's Cross (El Mirador), where the biggest flying bird in the world can usually be seen soaring amongst the peaks. There are also some picturesque colonial town around the rim of the canyon, like Yanque, Coporaque, Achoma and Maca.
Continuing northeast, you come into the Caylloma province, that possesses some of the highest satin-sheen lakes in South America like Lago Condoroma. As you come toward Espinar, no doubt you will think you are immersed in scenes of Lord of the Rings with the vast plains and swamps and mystic mountains in the hazy horizon.
You meet up with the Cusco-Puno highway at Combapata, where you will want to get off if you want to head to the beautiful city of Puno and Lake Titicaca in the south. I discuss stops on this highway in my route description Cusco - Puno, so I won't repeat it here, and instead I'll focus on Cusco itself, the capitol of the Inca Empire!
Beside Machu Picchu, there are other really interesting Inca archaeological sites immediately around Cusco. Q'inqu is one of them, and is the largest of the holy places in the region. Tambomachay is another, which is a terraced complex of aqueducts and canals and baths that were either for the Incan military or the elite. And then there's the piece-de-resistance, the massive Fortress of Sacsayhuaman that domineers over the city of Cusco from an overlooking hill, and has gigantic carved stones, some over 30ft high. The Inca Palace, Qurikancha, was sacked by the conquistadors, but the ruins of it are still there in the city and can be visited. more...
If you're coming from the splendid beach at El Rodadero in Santa Marta or visiting the Quinto de San Pedro Alejandrino where Simón Bolívar spent his last days, go west young packer on this Caribbean coastal route that involves just a couple hours ride at a time.
While most bypass the big industrial port of Barranquilla, it is South America's second Carnival capital (first being Río de Janeiro) at a much better bargain. It also is a great spot for art deco fans, including the Metropolitan Cathedral and the famous Teatro Amira de la Rosa museum and library.
Before you get to Cartagena, stop for an unforgettable experience at the Volcan de Lodo Totumo, a real volcano only about 30 feet high, that bubbles up lukewarm medicinal mud you can bathe and receive massages in, and then get yourself washed off in the nearby water -- very therapeutic and fun!
Cartagena itself is to die for, what I call the New Orleans French Quarter on Steroids! Old, full of pirate history, sultry and exotic. Sit on top of the old town wall more...
This is a splendid route that takes you from the capital (constitutional) of Bolivia through breathtaking highlands all the way to the gorgeous wine country of Tarija.
But before you leave Sucre going south, take a side trip east to what I think is Bolivia's best traditional market town, Tarabuco. On your way there, make sure to stop and walk with the dinosaurs at Cal Orcko, which contains over 5,000 tracks of 294 species of ancient beasts.
Going southward, your major "pitstop" worth spending at least a day in is Potosi, a town of intricately colored doorways and some of the best museums in South America thanks to its affluent history from mining. Climb the little hill of Tarapaya and find a natural thermal hot spring on the top waiting to give you a dip with a great view. Potosi is also a major crossroads for transporation going west to Uyuni.
Before you get to Tupiza, you might be tempted to just get off and do some hiking around the picturesque Laguna Kharachi Orcko, but if not wait to get into town where you'll find lots of outfitters to take you horseback riding or mountain biking through the area canyons and valleys. more...
My sweet spot for happy returns is to actually start this route in Misahuallí, a small town to the east of Tena where monkeys stroll around as casually as the people do. Then head north from Tena to go spelunking in the Jumandy Caves outside Archidona and some beautiful lodges and waterfall walks in nearby Cotundo.
If you want to imagine yourself in legendary adventure of Francisco Orellana and Pizarro to discover the source of the Amazon, hike the famous stone Guacamoyas Trail in Cosanga where they began.
Not much farther up the road is Ecuador's highest falls of San Rafael Falls near Salado, as well as Ecuador's most elusive and cranky volcano, El Reventador.
Great white water river rafting trips await you in the Quijos river region, and the best spot to scout for a local outfitter is Baeza (which is also the connecting point if you want to go back to Quito).
In Lago Agrio, which is mostly the entrance point for hiking into the huge Amozonian Cuyabeno Reserve, try to get there on a Sunday for the street market in which you can see the colorfully dressed Cofán people more...
If you're coming to Bolivia for the first or a short time, this route is likely the best pick. Cochabamba itself is a central hub for all directions, which makes it a good starting point, but we won't cover what to do there in this route.
Mizque is worth getting off the bus at least for a lunch break. It has a beautiful pink-trimmed church and a lazy river, and will give you a good idea of typical Bolivian highland life.
Next down the road is Aiquile, which is the center of making the small guitars used for Charango, a musical style very typical in this part of the Andes.
Your first big city stop will be Sucre, the constitutional capital of the country. Outside the city to the east is Cal Orkco, a collection of dinosaur footprints impressioned on a 70 degree wall of a cement quarry, which used to be a lake floor. "Dino Trucks" go there at 9:30AM, 12:00PM (noon), and 2:30PM from the corner of Plaza 25 de Mayo in front of the cathedral if they have a quota of 4 people. The guided visit takes about 1 hour, where from a viewing platform you can use binoculars to see the display of footprints on the landscape and some models of dinosaurs to give you context. more...