Formation of protein-ligand complexes causes various changes in both the receptor and the ligand. This review focuses on changes in pK and protonation states of ionizable groups that accompany protein-ligand binding. Physical origins of these effects are outlined, followed by a brief overview of the computational methods to predict them and the associated corrections to receptor-ligand binding affinities. Statistical prevalence, magnitude and spatial distribution of the pK and protonation state changes in protein-ligand binding are discussed in detail, based on both experimental and theoretical studies. While there is no doubt that these changes occur, they do not occur all the time; the estimated prevalence varies, both between individual complexes and by method. The changes occur not only in the immediate vicinity of the interface but also sometimes far away. When receptor-ligand binding is associated with protonation state change at particular pH, the binding becomes pH dependent: we review the interplay between sub-cellular characteristic pH and optimum pH of receptor-ligand binding. It is pointed out that there is a tendency for protonation state changes upon binding to be minimal at physiologically relevant pH for each complex (no net proton uptake/release), suggesting that native receptor-ligand interactions have evolved to reduce the energy cost associated with ionization changes. As a result, previously reported statistical prevalence of these changes - typically computed at the same pH for all complexes - may be higher than what may be expected at optimum pH specific to each complex. We also discuss whether proper account of protonation state changes appears to improve practical docking and scoring outcomes relevant to structure-based drug design. An overview of some of the existing challenges in the field is provided in conclusion.