Perforin (pfp) and interferon-γ (IFN-γ) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity. Using experimental (B6, RM-1 prostate carcinoma) and spontaneous (BALB/c, DA3 mammary carcinoma) models of metastatic cancer, mice deficient in both pfp and IFN-γ were significantly less proficient than pfp- or IFN-γ–deficient mice in preventing metastasis of tumor cells to the lung. Pfp and IFN-γ–deficient mice were as susceptible as mice depleted of natural killer (NK) cells in both tumor metastasis models, and IFN-γ appeared to play an early role in protection from metastasis. Previous experiments in a model of fibrosarcoma induced by the chemical carcinogen methylcholanthrene indicated an important role for NK1.1⁺ T cells. Herein, both pfp and IFN-γ played critical and independent roles in providing the host with protection equivalent to that mediated by NK1.1⁺ T cells. Further analysis demonstrated that IFN-γ, but not pfp, controlled the growth rate of sarcomas arising in these mice. Thus, this is the first study to demonstrate that host IFN-γ and direct cytotoxicity mediated by cytotoxic lymphocytes expressing pfp independently contribute antitumor effector functions that together control the initiation, growth, and spread of tumors in mice.