Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their protein targets. The approach followed in medicinal chemistry follows a combination of careful analysis of structural data together with experimental and/or theoretical studies on the system. This chapter focuses on the fact that a protein is not fully characterized by a single structure, but by an ensemble of states, some of them represent "hidden conformations" with cryptic binding sites. We highlight case studies where both experimental and computational methods have been used to mutually drive each other in an attempt to improve the success of the drug design approaches.Advances in both experimental techniques and computational methods have greatly improved our physico-chemical understanding of the functional mechanisms in biomolecules and opened a debate about the interplay between molecular structure and biomolecular function. The beautiful static pictures of protein structures may have led to neglecting the intrinsic protein flexibility, however we are entering a new era where more sophisticated methods are used to exploit this ability of macromolecules, and this will definitely lead to the inclusion of the notion in the pharmaceutical field of drug design.