Histone deacetylase 6 (HDAC6) is a maverick member of the Zn2+-dependent lysine deacetylase family of proteins collectively known as histone deacetylases (HDACs). Functionally, HDAC6 deacetylates non-histone substrates and regulates protein function, cytoskeletal dynamics, and cell migration. These roles are essential to cellular function and survival and have disease implicating consequences in several cancers and neurodegeneration. Interestingly, loss of HDAC6 function by inhibition, degradation, or deletion is well tolerated and HDAC6-knockout mice develop identically as wildtype mice. These combined attributes have made HDAC6 highly attractive to medicinal chemists and clinicians as an effective therapeutic target. However, a rational molecular design strategy for selectively inhibiting HDAC6 was not well defined, and most of these inhibitors achieved selectivity stochastically. This talk will describe a rational, iterative, and structural engineering strategy that identified a molecular template for reproducible, selective HDA6 inhibition. In addition to the canonical Zn2+-binding of traditional HDAC6 inhibitors, the lead chemotype in this study, resolved by x-ray crystallography, was revealed to accept an additional H-bond from the Zn2+-bound ligand, H614. This unique interaction with active site of HDAC6 presumably stabilizes binding conformation and improves inhibitor affinity. Extensive biological characterization of this new molecular template will also be described. This chemotype can be harnessed to further develop HDAC6-targeting compounds with promising preclinical profiles suitable for clinical translation.