The signals and niches that allow disseminated tumor cells (DTCs) to stay viable as metastasis-initiating seeds are largely unknown. An understanding of these mechanisms would help in developing treatments to eradicate DTCs and thus prevent metastasis. Recently we have identified signals that prime breast cancer stem cells for survival in distant organs. Activated SRC primes DTCs for a robust PI3K-Akt survival response to CXCL12 in the bone marrow. The leukocyte-tethering receptor VCAM-1 primes DTCs for PI3K-Akt activation by macrophage contacts in the lungs. The extracellular matrix protein tenascin-C (TNC) forms micrometastatic niches that promote WNT and NOTCH signaling in cancer stem cells. Lastly, a CXCL1-S100A8 paracrine loop protects DTCs from the stresses of metastasis and chemotherapy, providing a link for these two clinically related phenomena. In preclinical models, SRC kinase inhibitors, VCAM-1 blocking antibodies, and CXCL1 receptor inhibitors suppress metastasis and augment the efficacy of chemotherapy. SRC, VCAM-1, TNC and CXCL1 previously emerged in “metastasis gene signatures” that predict breast cancer relapse to distant organs. How is it that adaptive advantage traits for distant sites pre-exist in primary tumors? A newly identified “metastasis seed pre-selection” phenomenon addresses this old conundrum. We find that when the stroma of a breast tumor resembles that of a distant organ, it selects for cancer cells that are predisposed to thrive in that organ. In sum, niches and signals for DTC fitness can be identified, molecularly deconstructed, conceptualized, and therapeutically targeted.