Cancer cells contain significant alterations in their epigenomic landscape, which several enzyme families reversibly contribute to. One class of epigenetic modifying enzymes is that of histone deacetylases (HDAC), which are receiving considerable scrutiny clinically as a therapeutic target in many cancers. The underlying rationale is that inhibiting HDACs will reverse dysregulated target gene expression by modulating functional histone (or other) acetylation marks. This perspective will discuss a recent paper by Markozashvili and co-workers which appeared in Gene, which indicates that the mechanisms by which HDAC inhibitors (HDACis) alter the epigenetic landscape include widespread alternative effects beyond simply controlling regional epigenetic marks. HDACs are involved in many processes/diseases, and it is not surprising that HDACis have considerable off-target effects, and thus a major effort is being directed toward identification of inhibitors which are selective for HDAC isoforms often uniquely implicated in various cancers. This Perspective will also discuss some representative work with inhibitors targeting individual HDAC classes or isoforms. At present, it is not really clear that isoform-specific HDACis will avoid non-selective effects on other unrecognized activities of HDACs.