Recurrence of cancer in the form of metastatic disease accounts for more than 90% of cancer deaths; however, tumor metastasis is considered an inefficient process whereby disseminated tumor cells remain undetected for protracted periods of time. Remarkably little is known about processes that serve to convert indolent tumors – such as the metastases that disseminate from a primary tumor – into overt, life-threatening tumors. Our prior work lead to the discovery that certain indolent tumor cells can respond to systemic cues to become overt, detectable tumors. These systemic cues were actually generated by aggressively growing tumors located at distant anatomical sites. Thus, we found that human breast carcinomas (termed “Instigators”) facilitate growth of otherwise-indolent tumor cells and micrometastases (termed “Responders”) located in different anatomical sites within host animals. We termed this action-at-a-distance “Systemic Instigation”. Therefore, we think of cancer as a disease that is capable of actively perturbing as well as responding to the host systemic environment. The view that tumor cells escape detection and remain indolent for protracted periods is not limited to disseminated tumor cells, but can also apply to primary tumors. Our research is focused on identifying systemic factors that contribute to tumor progression and finding ways to interdict their function. It is our hope that such information will ultimately lead to new therapies to treat cancer patients.