An important mechanistic aspect of enzyme catalyzed amide bond hydrolysis is the specific orientation of the lone pair of the nitrogen of the scissile amide bond during catalysis. As discussed in the literature during the last decades, stereoelectronic effects cause the single lone pair in the formed tetrahedral intermediate to be situated in a non-productive conformation in the enzyme active site and hence nitrogen inversion or rotation is necessary. By discussing recent mechanistic findings in the literature relevant for the conformation of the lone pair of the reacting amide nitrogen atom, it will be demonstrated that nature has evolved at least two catalytic strategies to cope with the stereoelectronic constraints inherent to amide bond hydrolysis regardless of the fold or catalytic mechanism. One solution to the inversion problem is to stabilize the transition state of inversion by hydrogen bond formation; another is to introduce a concerted proton shuttle mechanism that avoids inversion and delivers a hydrogen to the lone pair. By using molecular modeling it is demonstrated that the H-bond strategy is general and can be expanded to include many amidases/proteases with important metabolic functions, including the proteasome. Some examples of the proton shuttle mechanism will also be mentioned. To complete the picture of efficient enzyme catalyzed amide bond hydrolysis, general interactions in the active site of these catalysts will be discussed. An expanded knowledge of the prerequisites of efficient amide bond hydrolysis beyond the oxyanion hole and the catalytic dyad/triad will be of importance for enzyme and drug design.