Protein-Protein (P-P) interactions play a pivotal role in determining cellular structure and in all cellular processes. The nature of P-P interactions is complex, and despite the large amount of research that has occurred in the field, is still poorly understood. Abnormal P-P interactions are particularly important because of their association with a variety of diseases, including cancer. This review examines P-P interactions with particular emphasis on the discovery of new anti-tumor drugs, including underlying physical forces that determine affinity and specificity and discusses classical and newer strategies used to discover inhibitors of P-P interactions, providing a number of recent cancer-related case studies and commentary.