In the nineteenth century, William B. Coley induced durable remission of inoperable metastatic sarcoma by repeatedly injecting live streptococcus bacilli and, subsequently, heat-killed bacterial extracts into the primary tumor. While Coley's contemporaries debated the veracity of his results, this bold treatment protocol established the new scientific field of immunology. In Coley's era, the scientific and medical communities lacked the prerequisite knowledge to validate and understand his treatment protocols. Today, a more comprehensive understanding of the human immune system, anchored by the discovery of the mammalian Toll-like receptor gene family in the 1990s, permits a mechanistic understanding of his results. Coley's cocktail of TLR agonists likely stimulated a complex cascade of cytokines, each of which plays a unique and vital role in the orchestration of the immune response. Here we explore Coley's legacy: a dissection of those cytokines which possess the immunostimulatory properties necessary to modulate the immune system and ameliorate human disease. The discussion is limited to molecules that have been able to show therapeutic promise in the clinical setting.