beta-Lactams are widely used in medicine as potent antibacterials and in chemistry as synthetic intermediates. The investigation of the intrinsic reactivity of beta-lactams is important for the understanding of the mechanisms of action and inactivation of beta-lactamases and penicillin-binding proteins. Ab initio quantum mechanical calculations using a polarizable continuum model to estimate solvation effects have been utilized to analyze the hydrolysis and methanolysis of selected beta-lactams and simple amides. The roles of four-membered ring strain, reduced amide resonance, substituent and ring fusion effects on hydrolysis, and methanol-mediated hydrolysis of these compounds have been studied by reconstructing the corresponding reaction pathways in gas and solution. Strong correlations have been found between the calculated kinetic, structural, and electronic properties of these compounds and the experimental data. The findings in this paper shed light on the contributions of the various structural elements to the reactivity of beta-lactams. Insights into this reactivity could prove very useful in the design of novel potent antimicrobials.