Tumor cells undergo senescence in response to both conventional and targeted cancer therapy. The induction of senescence in response to cancer therapy can contribute to unfavorable outcomes, potentially including cancer relapse. This work demonstrates that tumor cells induced into senescence by doxorubicin, etoposide, or radiation can give rise to viable tumors in vivo. We further demonstrate that exposure of senescent tumor cells to the senolytic ABT-263 (navitoclax) could represent a two-hit approach to suppress senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy-induced senescence and ABT-263 could shift the response to therapy towards apoptosis by interfering with the interaction between BCL-X and BAX. The administration of ABT-263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor-bearing animals. These results support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence.This article is protected by copyright. All rights reserved.