Living systematic reviews are a relatively new approach to keeping the evidence in systematic reviews current by frequent surveillance and updating. The Agency for Healthcare Research and Quality’s Evidence-based Practice Center Program recently commissioned a systematic review of plant-based treatments for chronic pain management. This white paper describes the team’s experience in implementing the protocol that was developed a priori, and reflects on the challenges faced and lessons learned in the process of developing and maintaining a living systematic review. Challenges related to scoping, conducting searches, selecting studies, abstracting data, assessing risk of bias, conducting meta-analysis, performing narrative synthesis, assessing strength of evidence, and generating conclusions are described, as well as potential approaches to addressing these challenges.