Biophysical methods are currently involved in drug design in two ways: the qualitative detection of small molecule binding to a target (hit identification), and the quantitative determination of physical parameters associated to binding (hit-to-lead progression). In the first case, efforts have been made toward miniaturization, automation, and speed-up of the screening process allowing a higher throughput. In the second one, sophisticated applications have been developed to derive detailed relevant information. Preferably, several methods are used in combination to avoid bias and/or limitations associated with a single one, often together with computational methods. New developments should allow important systems overlooked so far to be studied: membrane proteins, intrinsically unstructured proteins, as well as in-cell studies.