Note the photography collection and the rooftop honeybee hives as you check in to the Hotel Lucia in the heart of downtown. After you're settled, a walk through downtown is a great way to start your exploration.
If you've arrived during the weekend, it's only a short walk east to the riverfront and Saturday Market, the weekend street market under the Burnside Bridge and along the waterfront. Here you'll find local artists selling everything from handmade jewelry and pottery to handcrafted cat toys.
Once you've gotten your fill of the market, stroll down the waterfront a few blocks to Alder, then up to the SW 10th and Alder food cart pod, where you can grab a quick bite of a huge variety of cuisines at the largest concentration of street food in America. It's an essential Portland experience, as are the people watching opportunities around the pod.
Then it's time to continue south just five blocks to the Portland Art Museum, where you can wander in and out of collections and catch a public tour if you time it right. A good stop on the way is the beautiful main branch of the Multnomah County Library (famously mentioned in a Decembrists song).
For dinner, try Urban Fondue, an intimate restaurant in the neighborhood with a delicious assortment of cheese fondues, cooked-on-your-table entrées, and decadent desserts.
If you can time your visit to align with the first Thursday of the month, a good next stop is the Pearl district for First Thursday, a monthly art opening and gallery walk. Experience the finest Portland art galleries with some of the city's best art patrons, and join other gallery-goers for wine and conversation.
Then head over to Portland Center Stage's beautiful theater in the Pearl's armory building to catch the latest in unique Portland performance.
After the show, a cab ride back to your hotel will offer plenty of opportunities to hop out at whichever of the many downtown bars are most appealing - CC Slaughters is a good bet on any night.