Cancer cell repopulation after therapy is a phenomenon that leads to therapeutic failure with the consequent relapse of the disease. The process is understudied and mechanisms need to be uncovered. Here we discuss the issue of cancer cell repopulation after chemo- and radio-therapies. We compile evidence alleging that the repopulation of cancer cells can be originated from either cancer stem cells resistant to therapy, cancer cells that in response to therapy become polyploid and thereafter germinate into near-diploid rapid proliferating cells, and/or cells that respond to treatment undergoing senescence as a transient mechanism to survive, followed by the reinitiation of the cell cycle. Approaches targeted to prevent this post-therapy cancer cell repopulation should be uncovered to prevent tumor relapse and thus increase overall survival from this devastating disease.