Understanding the biological functions of proteins has been facilitated by the availability of powerful computational tools that greatly help analyzing the complex nature of protein structure-function relationships. The most important challenge faced by functional genomics and proteomics is to elucidate how the three-dimensional structure of a protein may change in vivo, and directly produce a new functional state. The key to understanding functional switches in proteins is to define how post-translational modifications contribute to the structural plasticity of those proteins and how new structures display new functions. Deciphering the protein functional switches regulated by transitory structural and conformational changes will require collaboration between computational scientists and experimentalists. The purpose of this review is to critically discuss the tools presently available in computational biology to approach these questions.