If you mean you have a 3d model and you want to paint directly on it, rather than painting on a flat 2d uv map, the serious choice is ZBrush. Why? Well, a quick visit to ZBrush Central will show you what the pro's are creating with it. It has limitations .. no layers yet, shaders can't be exported, and painting is done using 'projection' .. ie the model has to be static when you paint on it, using Projection Master. This means you can't pan around the model adding a dab here and a dab here. Instead you need to 'drop' the model, paint on the surface you can see, pick it up, rotate the model, drop it again, paint, pick up etc. It soon becomes intuitive, but isn't perfect. However, you can paint several effects at the same time .. displacement, cavity shading, colour, texture and an alpha bump all at the same time, for example. And using a recent (free!) plug in you can have a copy of Photoshop open and interactively alter your texturing in real time.

And for occasions when you want to paint a flat picture which looks like it's 3d, there's nothing to touch ZBrush.