Therapeutic proteins carry out the most difficult tasks in living cells. They do so by interacting specifically with other molecules. This requires that they fold to a unique and more stable conformation. A prerequisite for comprehending the folding processes in their immense complexity entails a thorough understanding of many weak interactions. The purpose of this review is to systematically study the role of weak interactions such as cation-π, C-H......π, N-H......π and O-H......π, in the set of 49 therapeutic proteins. The importance of many of these interactions (for example, cationic residues interacting with π system) is revealed by the higher degree of conservation observed for them in protein structures. These interactions are mainly formed by long-range contacts and significant percentage of cation-π, C-H......π, N-H......π and O-H......π interacting residues had one or more stabilization centers. Further, a comparison of conventional and nonconventional interactions in the present data set unambiguously highlights the significance of these weak interactions in the structural stability of therapeutic proteins. We propose that the incorporation of the entirety of these interactions leads to a more complete description of the problem, and that this could provide new perspectives and new possible answers. © 2011 International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg.