Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) and trichostatin A (TSA) are inhibitors of the Zn(II)-dependent class I and class II histone deacetylases (HDACs), which are enzymes that operate in concert with histone acetyltransferases (HATs) to regulate the acetylation status of the epsilon-amino group of lysine residues of nucleosomal histones in chromatin. An increased level of histone acetylation resulting from the SAHA or TSA inhibition of Zn(II)-dependent HDACs relaxes the chromatin structure and upregulates transcription. The links made in the 1990s between the inhibition of HDAC activity and the suppression of tumor growth have brought the design of HDAC inhibitors (HDACi) to the forefront of oncology research. SAHA has anticancer activity against hematologic and solid tumors and has been approved by the FDA for the treatment of cutaneous T-cell lymphoma. The increased molecular-level understanding of class I and class IIa HDACs from X-ray crystallography highlights differences in the residues distal to the active site and in the cavity size, which has implications for HDACi substrate specificity and enzyme mechanism. Results from HDAC-focussed activity-based protein profiling experiments may lead to the design of molecules that are class-specific HDACi.