To get your bearings, you need to know that no one refers to the city's main artery as Avenida George Washington. This is a palm-lined boardwalk open to the sea. The Guinness Book of World Records calls it "The Planet's Largest Disco" because of all the clubs found here. Locals call it El Malecón (sea wall), and it hugs the edge of the Caribbean for a total distance of 8km (5 miles). This is one of the dozen or so major boulevards of the city, and the most important one. Parading along this boulevard at night (beware of pickpockets) is the major nighttime activity of both locals and visitors.
Forget about street addresses. Presumably, buildings are assigned a number, but locals rarely use them. The way to find an address is to tie in a building you're seeking with either a landmark or else the major cross street.
Chances are your hotel will be along the Malecón. For sightseeing, however, most interest focuses on the Zona Colonial (Colonial Zone), the heart of the centuries-old city where Sir Francis Drake, and Columbus, once walked.
Running parallel to the Malecón, but inland from the Caribbean, is Avenida Independencia. This wide boulevard cuts through the Gazcue sector of town, coming to an end at Parque Independencia and its nearby Palacio Nacional, lying just west of Zona Colonial. Parque Independencia is "ground zero" for the denizens of Santo Domingo.
One of the city's most attractive districts is Gazcue, lying immediately to the west of Zona Colonial, south of the Avenida Bolivar, and north of the Malecón. This is an upper-middle-class neighborhood with tree-shaded sidewalks. It centers on Plaza de la Cultura, and includes a popular stretch of El Malecón within its boundaries. A number of museums are here, and chances are you'll be visiting the district.
Río Ozama separates the western or right bank of Santo Domingo from the left or eastern bank. Lying directly off the Avenida España, the two districts here are Villa Duarte and Sans Souci, with most interest focusing on the Columbus Lighthouse, which locals refer to as El Faro Colón, or "El Faro." This monumental and stately looking lighthouse, whose floor plan was inspired by the form of a giant cross, towers over the western end of Parque Mirador del Este, a stretch of woodland spanning the length of the barrios east of the river.
The city's outer barrios won't concern the average visitor. These include Villa Mella to the north, a dreary sector of thatch huts and concrete structures that locals call home. Villa Mella is different from the rest of the districts in that most of its population was largely descended from slaves from the Congo, and some of the old Congolese culture still lives on in music, religion, and language. A new subway line is in the process of being built, a north-south line that, when completed in what's presently the summer of 2012, will link the Villa Mella neighborhood with El Malecón.
A barrio of more interest to the average visitor is the wealthy, and in some cases, spectacularly wealthy, Arroyo Hondo, lying to the immediate northwest and the site of the much-visited Jardín Botánico (Botanical Gardens). Close to the city's heart, the area gets a lot less upscale the more you travel northward. A short distance to the east of the botanical gardens lies the Parque Zoológico (zoo).