If your experienced with PHP, I'd highly recommend litecommerce which runs on Drupal. It's relatively flexible to customize; it's extremely simple in the front-end - in fact I fell in love with litecommerce mainly because of its UI. Well, the community is not as active as other platforms, but the the drupal community can definitely make up for it. I believe it does utilize a plugin architecture. It has some pre-made plugins that you can use. Although a lot of common features need to be achieved with plugins, but they are quite accessible. One thing to note is that it only runs on PHP 5.3 or above.

And if you are more experienced with Python, you can find a lot of flexible platforms that run on Django.