The lysosomal cysteine proteases (cathepsin) are widely distributed among living organisms. The papain-like cathepsins have been implicated in a variety of physiological processes and their proteolytic activities may also be relevant to many human diseases. Three-dimensional models of the cysteine proteases human cathepsins K, S, H, and F were built by homology modeling based on the crystal structures of related enzymes like cathepsin L, papain, and actinidin, for instance. The structure models were found to have good stereochemistry, and meet reasonably well various criteria for validating the overall correctness of the structures. Moreover, the position and the conformation of the minichain as an essential part of the cathepsin H could be determined. As a result of an analysis of the electrostatic potentials on the molecular surface of the cathepsins B, L, K, S, H, and F and the determination of the favorable subsites of the active site of these enzymes new potent ligands (substrates and inhibitors) for the cysteine proteases cathepsins L, K, and F were designed. Based on docking studies the non-bonded interaction energies and the dissociation constants of the ligands with the cathepsins were calculated. The kinetic data confirm the design hypothesis about the substrate and inhibitory potency by experimental data of cathepsin ligand complexes.