Despite that chemotherapy represents the frontier cancer treatment today, aggregating evidence in pre-clinical animal models and small patient cohorts paradoxically suggests that certain cancers often elicit pro-tumorigenic and pro-metastatic phenotypes in response to standard chemotherapy regimens. This phenotype is now believed to occur through a cancer-mediated secretion of pro-inflammatory cytokines, chemokines and other mediators, collectively known as the “cytokine storm”, initially affecting the local tumor microenvironment, but subsequently released in peripheral circulation, where it elicits systemic tumor-promoting effects . Two recent, seminal studies in this context, the first by Karagiannis et al. (2017) in Science Translational Medicine , and the second by Gartung et al. (2019) in Proceedings of the National Academy of Sciences (PNAS) , have shed useful insights on the molecular mechanisms underlying the pro-tumoral shift of the tumor microenvironment upon treatment with chemotherapy. When appreciated individually, each study reveals a unique piece of the puzzle, but valued together, they offer an attractive model on how “chemotherapy-induced metastasis” is regulated at the microanatomical level.