Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are currently in advanced clinical trials for the treatment of cancer. Vorinostat (Zolinza, SAHA) is a hydroxamic acid approved for the treatment of patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. As part of an on-going effort to better understand the nature of the HDAC enzyme/inhibitor interaction and design highly effective HDAC inhibitors, we herein report the design, synthesis and HDAC inhibitory activity of a vorinostat-derived series of substrate-based HDAC inhibitors.