Reversible inhibitors are associated with fewer side effects than covalently binding ones and are, therefore, advantageous for treatment of conditions involving endogenous enzymes. Transition state analogue structures provide one design paradigm for such inhibitors; this paradigm seeks to exploit the capability of an enzyme active site to stabilise a transition state or associated intermediate. In contrast, structures that retain the functionality, and scissile bond of the substrate, can also act as reversible inhibitors; these are referred to here as substrate variants to distinguish them from substrate analogues. Their mode of inhibition depends on destabilisation of a reaction-path transition state or states. As the mode of destabilisation can be quite varied the scope to exploit substrate variants as reversible inhibitors is substantial. The two design paradigms are contrasted here and the case of substrate variants is delineated with a well-defined set of structures. These include the naturally occurring polypeptides BPTI (an inhibitor of a serine-based protease) and cathepsin propeptides (inhibitors of cysteine-based proteases) as well as the synthetic small-molecules cilastatin (an amide inhibitor of a zinc-based protease) and substituted mono- and tripeptides as inhibitors of cathepsins K and L.