Caspases are a family of aspartate-specific cysteine proteases that regulate cellular homeostasis through the mediation of apoptosis and inflammation. Despite keen interest in caspases as therapeutic targets for cancer, inflammatory, and neurodegenerative diseases, no active-site directed small molecule has yet succeeded in navigating human clinical trials. At the same time, recent biochemical and biophysical studies have revealed caspases to be highly dynamic proteases possessing a remarkable diversity of activation mechanisms. In addition, many caspases possess an allosteric circuit linking key active site loops with a distal allosteric site located at the dimer interface. Accordingly, small molecule binding at this allosteric site directly impacts structural organization of the active site and thus catalytic activity. Both cysteine-tethered and non-covalent reversible small molecules have recently been identified for these allosteric sites, with binding producing a variety of functional effects. Surprising new examples of caspase modulation have also been described recently, including a small molecule that binds caspase-6–substrate complexes uncompetitively and a short peptide that stabilizes an inactive, tetrameric form of procaspase-6. The confluence of recent biochemical, biophysical and pharmacological data has revealed exciting new avenues for the modulation of caspase activity via binding beyond the active site.