A cardinal feature of human cancers is the progressive selection and outgrowth of cells that possess increasingly aggressive properties. This process ultimately leads to resistance to therapeutic agents, distant metastasis, and tumor recurrence. Together, these three manifestations of tumor progression are responsible for the vast majority of cancer deaths. Nevertheless, while tumor progression constitutes a problem of unrivaled clinical importance, the mechanisms underlying it are largely unknown. As such, elucidating the molecular, cellular, and pathophysiological events that contribute to tumor progression is a critical priority in cancer research. To better define the genetic, cellular, molecular, and physiological events that contribute to breast cancer progression, we have created a series of novel inducible bitransgenic mouse models in which the oncogenes c-myc, Neu, Wnt1, v-Ha-Ras, and Akt1 can be conditionally expressed in the mammary epithelia of animals treated with tetracycline derivatives. Tumor formation in each of these models is highly penetrant, mammary-specific, and absolutely dependent on transgene induction by doxycycline. The properties of this model system permit the direct visualization and analysis of each stage of mammary tumorigenesis from normal mammary tissue in the uninduced state to hyperplasias, atypical hyperplasias, invasive carcinomas, and distant metastases that arise as a consequence of oncogene activation. The inducible nature of the transgenic models that we have developed permits essentially complete downregulation of an oncogenic stimulus within an intact tumor. Remarkably, we have found that–following transgene deinduction by doxycycline withdrawal–many of these oncogene-induced primary mammary tumors rapidly regress to a clinically undetectable state. However, despite this dramatic regression behavior, a substantial fraction of tumors that have previously regressed to a non-palpable state recur spontaneously in the absence of transgene expression over periods of up to 1 year. This finding suggests that many animals in whom tumors have regressed still harbor residual cancerous disease and that additional genetic events may occur in these remaining cells that lead to the recurrence of actively growing tumors. In addition, we have further demonstrated that a subset of primary mammary tumors fail to regress fully following doxycycline withdrawal, and instead acquire the ability to survive and grow in the absence of oncogene overexpression. In some cases, this behavior is associated with identifiable spontaneous genetic events that are tightly linked to the ability of tumors to progress to transgene independence. In aggregate, the tendency of mammary tumors in this system to metastasize, to develop resistance to oncogene downregulation, and to recur spontaneously with long latency suggests that these models mimic critical aspects of the natural history of human breast cancer. As such, this system may represent a valuable new means to understand the biology of tumor progression and to identify the molecular mechanisms by which mammary tumors escape their dependence on particular oncogenic pathways for growth.