14-3-3 is a family of highly conserved regulatory proteins which is attracting a significant interest due to its potential role as target for pharmacological intervention against cancer and neurodegenerative disorders. Although modulating protein-protein interactions (PPI) is still conceived as a challenging task in drug discovery, in past few years peptide inhibitors and small molecular modulators of 14-3-3 PPI have been described. Here we examine structural and biological features of 14-3-3 and propose an overview on techniques used for discovering small molecular inhibitors and stabilizers of 14-3-3 PPI.