Consolidation of the literature using systematic reviews is a critical way to advance a discipline and support evidence-based decision-making in healthcare. However, unique challenges exist that impact the conduct of systematic reviews in implementation science. In this commentary, we reflect on our combined experience to describe five key challenges unique to systematic reviews of primary implementation research. These challenges include (1) descriptors used in implementation science publications, (2) distinction between evidence-based interventions and implementation strategies, (3) assessment of external validity, (4) synthesis of implementation studies with substantial clinical and methodological diversity, and (5) variability in defining implementation ‘success’. We outline possible solutions and highlight resources that can be used by authors of primary implementation research, as well as systematic review and editorial teams, to overcome the identified challenges and optimise the utility of future systematic reviews in implementation science.