This brief review attempts to define the SSAR of two families of cytochrome P450. With P4502D catalytic competence is achieved by tight ionic binding which gives the enzyme high regioselectivity. In contrast P4503A achieves catalytic competence by a flexible binding site relying on hydrophobic forces that allow chemically vulnerable sites to be the principal sites of metabolism. In general, the different binding mechanism should be reflected in the enzyme, such that substrates of P4502D should have lower Km values than substrates of P4503A. Thus, routes of metabolism catalysed by P4502D may be saturated at substrate concentrations lower than routes catalysed by P4503A. The apparent differences between P4502D and P4503A in terms of substrate specificity bring into question what relationships govern other families of cytochrome P450. Our analysis of data suggests that the other principal form involved, generally, in the metabolism of pharmaceuticals in humans is P4502C9 (possibly 2C8 and 2C10). The enzyme is responsible for the metabolism of phenytoin, tolbutamide, tienilic acid , naproxen, ibuprofen, diclofenac , the 7-hydroxylation of S-warfarin  and the 7-hydroxylation of delta 1-tetrahydrocannabinol . These compounds all have areas of strong hydrogen bond  forming potential (Fig. 8), all distanced 5-10A from the site of metabolism. Moreover the carboxylic acid function of naproxen, ibuprofen and diclofenac (pKa 4.5) and the sulfonylurea of tolbutamide (pKa 5.4) render the compounds ionized at physiological pH. The ionised group is positioned 7-11A from the site of metabolism. It is likely, therefore, that hydrogen bonding and possibly ion-pair interactions play a major role in determining the SSAR of the P4502C isoenzymes. These interactions would suggest that the P4502C enzymes are analogous to P4502D rather than P4503A. In this regard it is noteworthy that P4502C9 is selectively and potently inhibited by sulfaphenazole (IC50 of 0.6 microM), a compound that is structurally related (Fig. 8) to the substrates in terms of potential hydrogen bonding regions [4, 41]. Simplistically we suggest that the SSAR of the various P450 enzymes ranges from the highly selective enzymes dealing with endogenous substrates, through the enzymes metabolising exogenous substrates with narrow substrate structure requirements such as P4502D to P4503A with its broad substrate structure range. It would seem logical that animals and humans would evolve such combinations of isoenzymes to deal with the vast array of exogenous xenobiotics.