Cancer has become one of the leading causes of morbidity and mortality worldwide. This disease is classified broadly by tissue, organ, and system; different cancer types and subtypes require different treatments. Drug bioavailability, selectivity, and high dosage, as well as extended treatment, are significantly associated with the development of resistance – a complex problem in cancer therapy. It is expected that the combination of anticancer drugs and drug delivery systems, using polymers to increase the access of such agents to their site of action, will improve the efficacy of therapy. Polyethyleneimine (PEI) is a polymer used as a co-delivery system for anticancer drugs and gene therapy. PEI is also useful for other purposes, such as transfection and bio-adsorbent agents. In co-delivery, PEI can promote drug internalization. However, PEI with a high molecular weight is linked to higher cytotoxicity, thus requiring further evaluation of clinical safety. This review focuses on the utilization of PEI as a co-delivery system for anticancer therapy, as well as its potential to overcome resistance, particularly in the treatment of specific subtypes (eg, breast cancer). In conclusion, PEI has promising applications and is improvable for the development of anticancer drugs.