It is still hard to believe that manipulation of a single protein on the cell surface or an interaction of two or more proteins, which at times is collectively referred to as a “pathway,” could have such a profound effect on our immune system. At present, a number of such proteins or pathways have been identified. These observations could only be interpreted in a way that, although tens of thousand of proteins are required for a perfectly healthy immune system, many of these pathways may work in either interconnected or linear fashion. Therefore, the combined understanding of each pathway, their interactions with other pathways, and the functional c- sequence, is a cornerstone for our interpretation of pathological basis of diseases and future treatments. It is important to stay abreast on the pace of progress, which I refer to as periodic summary of incremental and breakthrough discoveries in each pathway by the experts and the leader in the field. The CD137 Pathway: Immunology and Diseases represents such an effort and this is the first attempt to summarize our understanding of the CD137 pathway. The following chapters cover the majority of active areas of research in this pathway and also provide an essential resource to both the nonexperts and experts in the field.