Intcrleukin-16 (IL-16) was originally identified in 1980 as the first-described T-cell chemoattractant. Since that time, the protein has been cloned, sequenced, and characterized in terms of expression and biologic function for regulating inflammation. Generated as a precursor molecule, IL-16 is cleaved by caspase-3, yielding pro-IL-16 and the secreted (mature) portion. Both components of IL-16 are now known to regulate T-cell growth and represent one of the few proteins for which function has been determined for both the pro-and secreted portions. Secreted IL-16 primes CD4+ T cells for IL-2 and IL-15 responsiveness, with a preferential effect on T H 1 cells. Animal models have identified its involvement in the establishment of T H 1-type inflammation with a critical role in the development of certain autoimmune diseases. Nuclear pro-IL-16 is a recently identified regulator of Skp2 transcription and T-cell cycle progression, acting as a scaffold protein for GABPβ and histone deacctylase-3. The intent of this review is to present an update on the structure of both IL-16 and pro-IL-16, the biologic functions of both components, and how the functions relate to the pathology of certain diseases where changes in IL-16 expression levels have been detected.