In this chapter we investigated which hand gestures are intuitive to control a large display multimedia interface from a user’s perspective. Over the course of two sequential user evaluations, we defined a simple gesture set that allows users to fully control a large display multimedia interface, intuitively. First, we evaluated numerous gesture possibilities for a set of commands that can be issued to the interface. These gestures were selected from literature, science fiction movies, and a previous exploratory study. Second, we implemented a working prototype with which the users could interact with both hands and the preferred hand gestures with 2D and 3D visualizations of biochemical structures. We found that the gestures are influenced to significant extent by the fast paced developments in multimedia interfaces such as the Apple iPhone and the Nintendo Wii and to no lesser degree by decades of experience with the more traditional WIMP-based interfaces.