The preclinical development of anticancer drugs has been based primarily on the transplantation of murine or human cancers into mice. Alternatives to these transplantation models are animals that naturally develop cancers with features relevant to the human disease. The first group of these models arises in mice that are genetically engineered to develop cancer. The second group includes pet dogs and cats that naturally develop cancer. This review will discuss the use and integration of these spontaneous cancer models into a comprehensive and comparative approach to preclinical drug development. Examples of their successful use and an outline of their relative strengths and weaknesses will be provided.