The identification and characterization of the first potent histone deacetylase inhibitors constituted a major step, which not only gave a key to researchers worldwide to tackle the unknown universe of cell signalling by protein lysine acetylation, but also opened the way for the development of large series of molecules with important therapeutic properties. Minoru Yoshida, who played a critical role in characterizing the fist potent and specific histone deacetylase inhibitor, trichostatin A, reveals here how and why his work led to this discovery. He also comments on his other outstanding contributions and gives his opinion on the impact of chemical genomics as a key to open the mysteries of the epigenome.