Depent how long you are going. For a first time, most people would do Tokyo/Kyoto. It's also possible to stay around Tokyo only and do "side trip" like Nikko, Kamamura, Hakone, same idea fot Kyoto with Nara, Osaka, Kobe, Himeji.
Some people would prefer to go further, like Hiroshima, it really depend on what you want to see and what you want to do. Do you want to see the modern side of Japan, to buy anime related stuff, or a more traditionnal Japan, with old buildings and countryside ?
For a first time, I would say that it's easier if you can stay several day in the same place.
Meijijinggu in Harajuku is a must-visit landmark in Tokyo. It is an oasis of green at the heart of the city. It is breathtaking to walk through the huge trees and experience the quiet of the shrine. Then when you're done, Omotesando, Yoyogi and Harajuku are all walking distance from there.