Despite an abundance of clinical and basic science research, anterior knee pain syndrome or patellofemoral pain syndrome (PFPS) remains, according to John Insall, an orthopedic “enigma” (“Black hole of Orthopedics”). The numerous treatment regimes that exist for PFPS highlight the lack of knowledge regarding the etiology of the pain. At present, no theory provides a comprehensive explanation of the true nature of this pathologic condition or how to hasten its resolution in a safe and reliable way. This chapter reviews the literature and synthesizes our research on anterior knee pain pathophysiology. This topic is clinically relevant because patient management will be greatly simplified when we understand what the causes are for anterior knee pain in the young patient.