An increasing number of people living with HIV (PLHIV) are failing treatment without HIV drug resistance in the drug target region. While sub-optimal adherence is likely the cause of treatment failure in many PLHIV, resistance emerging at non-canonical (HIV drug resistance mutations occurring outside the drug target site) drug target site sites is also plausible. Non-canonical drug resistance mechanisms have been identified for integrase strand transfer inhibitors (INSTIs), protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. Overall, they may act by i) restoring viral fitness caused by mutations in the drug target sites, ii) enhance resistance when occurring with mutations at the drug target sites iii) independently cause resistance even in the absence of drug resistant mutations (DRMs) at the drug target site iv) prime the emergence of resistant variants with DRMs at drug target sites. However, the clinical relevance of non-canonical resistance mechanism beyond in vitro and small in vivo studies is still needed and could include the assessment of such mechanisms in clinical trials and implementation studies. This information would be vital in guiding effective management of PLHIV with viral non-suppression despite good adherence as well as informing public health surveillance strategies.