The rapid developments in biotechnology create a great demand for fluid handling systems on the nano- and picoliter scale. The characterization of minute quantities of DNA or protein samples requires highly integrated, automated, and miniaturized total analysis systems (-TAS). The small scales necessitate new concepts for devices both from a technological and from a fundamental physical point of view. Here, we describe recent trends in both areas. New technologies include soft lithography, chemical, and topographical structuring of surfaces in order to define pathways for liquids, as well as electrowetting for manipulation purposes. Fundamentally, the interplay between geometric confinement and the size of biological macromolecules gives rise to complex dynamic behavior. The combination of both fluorescence imaging and scattering techniques allows for detailed insight into the dynamics of individual molecules and into their self-assembly into supramolecular aggregates.