Background and aims: This review aimed to describe factors associated with HAART non-adherence and did focus on the HIV/AIDS situation and antiretroviral therapy. Methods: The strategy of this review adopted a critical approach to reduce the bias of published or non-published information. Only evidence-based information was used from PubMed, Embase, Medline, and Google scholar. However, relevant grey information from monography/technical reports or specific books was also used. Results: Findings were out lighted across the global status of HIV epidemic, HIV/AIDS epidemic in Sub-Saharan Africa, history of HIV and ART in South Africa, HIV infection and antiretroviral therapy, HIV life cycle, HIV treatment, Highly Active Antiretroviral Therapy, Adherence to HAART, and factors associated with HAART non-adherence. The reviewed literature revealed consistency in important factors associated with HAART nonadherence across multiple settings and countries. Conclusion: This review was to determine factors associated with nonadherence with highly active antiretroviral therapy among HIV-infected patients attending Lerato clinic in Gauteng, South Africa. The reviewed factors leading to non-adherence will be submitted to policymakers, health care workers in general, and Family medicine staff in particular.