The discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor at present in Phase I clinical trials for cancer, is described. Emphasis is placed on the specific hurdles overcome throughout the discovery process that relate to the nature of the targeted protein-protein interaction (PPI). This review draws on observations from the experience of discovering ABT-263 and discusses them within the framework of the larger issue of discovering drugs targeting PPIs. Issues discussed include the 'hot spot' paradigm, hit and lead generation, serum protein binding, structure-based design, and in particular, hydrophobicity and molecular size and their relation to pharmacokinetic/pharmacodynamic properties. Approaches to understanding obstacles thought of as being specifically attached to PPIs, and existing techniques to combat these obstacles, were very helpful in overcoming them. The example of ABT-263 provides evidence that the larger family of PPI targets is more tractable than may have been thought.