The interest in histone deacetylase (HDAC) inhibitors began almost 30 years ago during some studies designed to understand why dimethyl sulfoxide (DMSO) caused terminal differentiation of murine erythroleukemia cells. This early observation paved the way for the development of novel pharmacological agents in the field of chromatin remodeling. In October 2006 the FDA approved the first HDAC inhibitor, SAHA (Figure 1), to treat the rare cancer cutaneous T-cell lymphoma (CTCL), and in the meantime there has been an aggressive development effort to bring HDAC inhibitors to the market for every major tumor type, both solid and hematologic, either as a single therapy or in combination, and a number of molecules are currently undergoing clinical trials (Figure 1). These compounds owe their antitumor action to their ability to reverse some of the aberrant epigenetic states associated with cancer. In spite of this, the mechanisms that underlie these effects are far from being completely elucidated. The research in this domain is intense, and our understanding of the biology involved is rapidly increasing. Beyond cancer, novel additional therapeutic applications, such as neurodegenerative diseases and inflammation, have been proposed for histone deacetylase inhibitors. A number of reviews has appeared recently in literature on HDAC inhibitors, mainly on the pharmacology and on the patent issues. In this review we specifically focus on the medicinal chemistry efforts carried out in the field since the Miller paper of 2003, with some additional considerations concerning the biology and the pharmacology of these molecules.