'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-γ (IFN-γ) is known to be involved in this process, the involvement of type I interferons (IFN-α/β) has not been elucidated. We now show that, like IFN-γ, endogenously produced IFN-α/β was required for the prevention of the growth of primary carcinogen–induced and transplantable tumors. Although tumor cells are important IFN-γ targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-α/β targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-γ.