The semiempirical molecular orbital procedures MINDO/3, MNDO, MNDO/M, AM1, and PM3 have been used to examine possible mechanisms and modes of attack of methanol on penam, the bicyclic ring system of penicillin. These mechanisms include a one-step process in which C—O bond formation from the convex face of the molecule and proton transfer to the β-lactam nitrogen are concerted with the cleavage of the N—C(O) bond (the N-protonated pathway), and two O-protonated pathways, viz., addition to the β-lactam carbonyl group from the convex face and from the concave face of the bicyclic ring system. Only MINDO/3 reproduces the ab initio MP2/6-31G*//3-21G* trends, that the N-protonated pathway is energetically preferred over either O-protonated pathway, and, in the latter, attack from the convex face is slightly preferred over attack from the concave face. MINDO/3 has, therefore, been used for a systematic examination of the reactions of many substituted and unsubstituted β-lactam-containing ring systems with methanol. The N-protonated structure created by attack of the alcohol from the convex face of the molecule is always preferred, and structure–reactivity relationships are observed that parallel structure–activity relationships of β-lactam antibiotics. MINDO/3 has also been used to compute a scaled quantum mechanical force field for Δ2- and Δ3-cephems. This has allowed parameters to be proposed for Δ2- and Δ3-cephems in the force field of Allinger's MMP2(85) programme that complement earlier parameterizations of the program for penicillins and peptides. The availability of these parameters has led to the development of a protocol for the analysis of the differences in the antibacterial activities of penicillins and cephalosporins. The analysis is based on a combination of "fit" and "reactivity" at the site of action. Fit is determined from the geometry that results when the β-lactam compound is complexed to a hexapeptide model of the penicillin receptor, in particular, the four-centred interaction between C-O-H of the active site serine residue and (O)C-N of the azetidinone ring. Reactivity is derived from MINDO/3 calculations of ΔE≠ for the reaction of methanol with the different ring systems via the N-protonated pathway. Δ3-Cephalosporins are suggested to be inherently less active than penicillins because they are inherently less reactive. Δ2-Cephalosporins containing a 4α-oriented carboxyl group are much less active than Δ3-cephalosporins because they have a much poorer fit. The 4β epimers of these Δ2-cephalosporins are much less active than Δ3-cephalosporins because they are much less reactive.