Mechanisms of host defense can form an unwitting alliance with tumor cells to promote tumor progression, invasion, and dissemination to distant sites. By secreting TGF-beta, an immunoregulatory molecule designated for both promoting inflammation and dampening immune responses, the tumor tricks the host into supporting its expansion and survival. TGF-beta not only recruits leukocytes to secrete chemokines, growth factors, cytokines, and proteases in support of a tumor-friendly niche but also in a context-specific manner, incapacitates the emergent immune response. As a profound immunosuppressant, TGF-beta, both directly and through the generation of regulatory T cells, blunts immune surveillance, favoring tumor escape. Collectively, the ability of the tumor to hijack these host defense pathways can tip the balance in favor of the tumor.