Recent success stories concerning the targeting of protein-protein interactions (PPIs) have led to an increased focus on this challenging target class for drug discovery. This article explores various avenues to assess the druggability of PPIs and describes a druggability decision flow chart, which can be applied to any PPI target. This flow chart not only covers small molecules but also peptidomimetics, peptides and conformationally restricted peptides as potential modalities for targeting PPIs. Additionally, a retrospective analysis of PPI druggability using various computational tools is summarized. The application of a systematic approach as presented in this paper will increase confidence that modulators (e.g., small organic molecules or peptides) can ultimately be identified for a particular target before a decision is made to commit significant discovery resources.