Over the past decade, T cell immunotherapy has changed the face of cancer treatment, providing robust treatment options for several previously intractable cancers. Unfortunately, many epithelial tumors with high mortality rates respond poorly to immunotherapy, and an understanding of the key impediments is urgently required. Cancer-associated fibroblasts (CAFs) comprise the most frequent nonneoplastic cellular component in most solid tumors. Far from an inert scaffold, CAFs significantly influence tumor neogenesis, persistence, and metastasis and are emerging as a key player in immunotherapy resistance. In this review, we discuss the physical and chemical barriers that CAFs place between effector T cells and their tumor cell targets, and the therapies poised to target them.