The specificity of immunoglobulins and α/β T cell receptors (TCRs) provides a framework for the molecular basis of antigen recognition. Yet, evolution has preserved a separate lineage of γ/δ antigen receptors that share characteristics of both immunoglobulins and α/β TCRs but whose antigens remain poorly understood. We now show that T cells of the major tissue γ/δ T cell subset recognize nonpolymorphic CD1c molecules. These T cells proliferated in response to CD1⁺ presenter cells, lysed CD1c⁺ targets, and released T helper type 1 (Th1) cytokines. The CD1c-reactive γ/δ T cells were cytotoxic and used both perforin- and Fas-mediated cytotoxicity. Moreover, they produced granulysin, an important antimicrobial protein. Recognition of CD1c was TCR mediated, as recognition was transferred by transfection of the γ/δ TCR. Importantly, all CD1c-reactive γ/δ T cells express Vδ1 TCRs, the TCR expressed by most tissue γ/δ T cells. Recognition by this tissue pool of γ/δ T cells provides the human immune system with the capacity to respond rapidly to nonpolymorphic molecules on professional antigen presenting cells (APCs) in the absence of foreign antigens that may activate or eliminate the APCs. The presence of bactericidal granulysin suggests these cells may directly mediate host defense even before foreign antigen-specific T cells have differentiated.