Systematic review is a type of rigorous, evidence-based analysis for answering a specific research question. This methodology is rapidly being implemented globally in the field of toxicology, though is often met with resistance due to the resources required to conduct a high quality review. The objective of this presentation is to provide a demonstration of the rigor and resources required to conduct full systematic reviews in toxicology with the aim of helping practitioners to determine when such a review is needed. A systematic review of caffeine safety in healthy adults, pregnant women, adolescents, and children will be used as a case study to demonstrate key elements of conducting a systematic review according to standards from the Institute of Medicine. Broad in scope, this systematic review addresses five PECO questions and integration of >380 papers to develop conclusions. This case study will highlight the role of problem formulation in determining if and when a systematic review is needed, as well as the protocol development and topic-specific refinements needed for the application of systematic review methodologies originally developed for clinical medicine. The case study on caffeine will also address the utility of multidisciplinary teams, implementation of a priori methods, and application of systematic review to a very large evidence base. It will also highlight the need for refined guidance and frameworks unique to the conduct of systematic review (e.g., multi-endpoint reviews) in the fields of toxicology and risk assessment. Using other case studies, additional elements of systematic review which are commonly underappreciated will be addressed, including appraisal and integration of study validity via risk of bias, evaluation and integration of multi-stream evidence bases ([including mechanistic data], and application of such concepts in qualitative vs. quantitative assessments). Collectively, the case studies will characterize the rigor and resources required for the conduct of high quality systematic reviews—practical information needed for toxicologists and risk assessors to understand the benefits and challenges of conducting meaningful systematic reviews in the fields of toxicology and risk assessment.