Heat-shock proteins (HSPs) play a crucial role in maintaining protein stability for cell survival during stress induced insults, including those caused by cytotoxic chemotherapy. In addition to cell survival aided by protein stability, HSPs overexpression in cancer cells result in anti-apoptotic activity contributing to cancer cell survival. Cytotoxic chemotherapy continues to play an important role in the treatment of many cancers, including triple-negative breast cancer (TNBC). First-line therapy for TNBC include anthracycline antibiotics, which are associated with serious side-effects and dose-dependent resistance. Preliminary studies identified YDJ1, which encodes a heat-shock 40 protein (HSP40), an important factor in the cellular response to anthracycline antibiotics. Mutants of the YDJ1 gene display >100-fold increased sensitivity to doxorubicin. To determine the role of DNAJAs in the cellular response to cytotoxic drugs, we investigated their ability to rescue ydj1 mutants from exposure to chemotherapeutic agents. Our results indicate that DNAJA1 and DNAJA2 provide distinct levels of protection, while DNAJA3 and DNAJA4 were heterologous. The level of complementation was also dependent on the agent used. There is a unique significance in DNAJA1 and especially DNAJA2 response to cellular stress when exposed to stressors that induce ROS, such as doxorubicin and menadione. There was no major significance in the sensitivity of all strains to etoposide. DNAJA3 and DNAJA4 were further evaluated for interference by the transformation of the WT containing a heat-shock gene. Data confirmed protein interference based on heterologous expression when exposed to heat-shock and doxorubicin. These data indicate that the DNAJAs play a role in the protection of cells from cytotoxic stress and may serve as targets to hypersensitize cells to cancer therapy, allowing for lower doses of treatment with a concomitant reduction of side effects.