Studies with perforin‐deficient mice firmly established perforin as a key element in cytotoxic T cell (CTL) / natural killer (NK) cell‐mediated tumor control but did not reveal the role of granzyme (gzm) A and B. A contribution of gzm in these processes was indicated by earlier in vitro experiments employing purified effector molecules demonstrated that tumor cell apoptosis and death only occurred in the presence of both, perf and gzm. However, recent work using mice deficient in either gzmA, gzmB or both gzm suggested that only perf but neither of the two gzm are criticalfor tumor surveillance by CTL or NK cells. In light of the conflicting results we have re‐investigated this issue by analyzing the potential of mice deficient in one or more component(s) of the exocytosis pathway to control NK‐sensitive syngeneic MHC class I‐defective RMA‐S tumor cells in vivo. Our results show that in contrast to wild‐type mice, mice deficient for both gzm exhibit an uncontroled tumor growth with a time kinetic similar to that of perforin‐deficient mice. Together with the finding that a defect of mice in either gzmA or gzmB alone also leads to an increased susceptibility to tumor growth, at least to a certain extent when compared to wild‐type mice, the data clearly indicate that a concerted action of perforin and the two gzm is mandatory for optimal NK cell‐mediated tumor control in vivo. Most notably, the in vivo potential of the respective NK cell populations was only reflected by their nucleolytic, but not their cytolytic activities in vitro.