The thermodynamics of ligand-protein binding has received much attention recently. In the present contribution we focus on the enthalpic component of binding. The dissociation constant, pK(d), was decomposed into enthalpic and entropic components (pK(d) = pK(H) + pK(S)), and pK(H), defined as pK(H) = -ΔH/(2.303·RT) was used to characterize the enthalpy contribution to binding. It was found that the maximal achievable pK(H) decreases with increasing molecular size. This is in contrast to maximal pK(d) that increases with molecular size until it achieves a plateau. Size-independent enthalpic efficiency (SIHE) was defined as SIHE = pK(H)/40·HA(0.3), with HA being the number of heavy atoms. SIHE allows a size unbiased comparative binding characterization of compounds. It can find use in hit and lead selection and also in monitoring optimization in drug discovery programs. The physical background of decreasing maximal pK(H) with molecular size is discussed, and its consequences to drug discovery are analyzed. It is concluded that the feasibility of simultaneous optimization of affinity and enthalpy diminishes with increasing molecular size. Consequently, binding thermodynamics considerations are to be applied primarily in hit prioritization and hit-to-lead optimization.