Natural killer (NK) cells may modulate the development of adaptive immune responses, but until now there has been little evidence to support this hypothesis. We investigated the primary and secondary immunity elicited by various tumor cell lines that express CD70 and interact with CD70 ligand (CD27), which is constitutively expressed on NK cells. CD70 expression enhanced primary tumor rejection in vivo as well as T cell immunity against secondary tumor challenge. Primary rejection of major histocompatibility complex (MHC) class I–deficient RMA-S.CD70 tumor cells was mediated by NK cells and perforin- and interferon-γ–dependent mechanisms. This NK cell–mediated process also efficiently evoked the subsequent development of tumor-specific cytotoxic and T helper type 1 responses to the parental, MHC class I–sufficient, RMA tumor cells. Thus CD27-CD70 interactions provide a key link between innate NK cell responses and adaptive T cell immunity.