Treatment of stage IV cancer, when metastases are detectable by conventional imaging methods, is commonly the only strategy we have to defend against this lethal stage of disease. However, the seeds of those lesions, the disseminated cancer cells (DCCs), can reside in a patient's organs for long periods before their outgrowth (1). DCCs are proposed to be able to persist for years because they interpret homeostatic signals from the host microenvironment and respond by entering a long-lasting dormant state, with occasional cell divisions (1, 2). In response to signals not yet fully identified, dormant DCCs reawaken and grow into larger lesions. So why not intervene earlier when DCCs are dormant? This has presented a challenge because the biology of DCC dormancy was mechanistically unclear and there was no way to determine whether DCCs were dormant. However, two decades of mechanistic research (1, 2) and recent work by Pommier et al. (3) and on page 1353 of this issue by Albrengues et al. (4) have provided important insights into the microenvironmental control of DCC dormancy and reawakening that leads to metastasis, which could have therapeutic implications.