The synthesis of several new oxorhenium(V) complexes containing the ‘3+1’ mixed-ligand donor set, ReO(SXS)(SR) (where X=S, O, N(R′); R=alkyl, aryl, heterocylce; R′=H, alkyl, aryl), is described. The X-ray structure for four of these complexes ReO(SN(Ph)S)(SPh) (6), ReO(SN(CH 2 CH 2 NMe 2 )S)(SPhOMe-p) (10), ReO(SOS)(SPh) (29) and ReO(SOS)(SPhNO 2 -p) (30) was determined. The inhibitory activity of all of the oxorhenium(V) complexes reported herein was evaluated against the cysteine proteases cathepsin B and K in vitro. Compound 25, ReO(SSS)(S-4py)·HCl, was the best inhibitor of the series against cathepsin B with an IC 50 of 10nM. Several of the complexes exhibited specificity for cathepsin B over K, suggesting that oxorhenium(V) complexes can be designed to be enzyme specific. The results described in this paper show that the oxorhenium(V) ‘3+1’ complexes are potent inhibitors of cathepsin B and K, constituting promising potential for the treatment of cancer and osteoporosis, respectively.