Histone deacetylases (HDAC) are a family of closely related enzymes involved in epigenetic and posttranscriptional regulation of numerous genes and proteins. Their deregulation is associated with a number of diseases, and a handful of HDAC inhibitors have been approved for cancer treatment. None of these entities, however, exhibit selectivity for a specific human HDAC. Recent structural insights into human HDACs may provide new strategies to achieve selectivity. In this Perspective, we discuss the binding modes of various HDAC inhibitors and highlight topological differences between enzymes as well as key, functionally important, features. Based on this analysis, we suggest alternative strategies to achieve selective HDAC inhibition that does not rely on chelation of the zinc ion in the active site but rather on disruption of protein-protein interactions important for HDAC activity. We believe that, although technically more challenging, these strategies will yield selective small-molecule HDAC modulators for use in basic research and in clinic.