The United States FDA approved 85 New Molecular Entities (NMEs) during the period from January 2001 to November 2004 of which 60 were pharmaceuticals with known molecular targets. The majority targeted enzymes (48%) or G-protein coupled receptors (GPCRs) (33%). Eighty percent of the NMEs interacted at the same site as endogenous effector; either as competitive inhibitor/antagonist (67%) or agonist (13%). Three biochemical operations defined the modes of action of the NMEs: 1) mass action competition (equilibrium), 2) a drug stabilized conformational change in the target that is important to the response (conformational) and/or 3) drug action is less-responsive to mass action competition with effectors due to non-equilibrium kinetics (non-equilibrium kinetic). Approximately 80% of the NMEs elicit a response utilizing conformational and/or non-equilibrium kinetic mechanisms. The remaining 20% of NMEs find mass action competition with the endogenous substrate or ligand sufficient for therapeutic utility. These observations indicate that for the majority of drug targets, mass action driven equilibrium binding alone may not be sufficient for maximal therapeutic utility. A key determinant of the biochemical mode of action for these NMEs was to minimize the potential for toxicity, either by providing a maximal response at a low dose to minimize off-target toxicities, or by providing a mechanism to minimize the incidence of mechanism-based toxicity while retaining a sufficiently efficacious response. This principle appears to be independent of target class and provides insight as to intrinsic biochemical features and approaches required for a maximal therapeutic index.