The Multi-skilled Resource Constrained Project Scheduling Problem (MS-RCPSP) is a complex and multi-faceted problem that involves scheduling activities whilst considering various resource constraints. These constraints include limited availability of workers, equipment, and materials, with each activity requiring a minimal set of skills to be executed. Furthermore, for a better resemblance to reality, workers/machines are assumed to be multi-skilled/multi-purpose posing another dimension of complexity to the problem. The objective is to minimize project duration, cost, or other relevant criteria while accounting for the inherent resources flexibility. This paper provides a systematic review of the literature pertaining to MS-RCPSP, and an in-depth analysis of 171 papers published between 2000 and 2021 inclusive. The conducted bibliometric analysis identifies the top contributing authors, most influential papers, existing research tendencies, and thematic research topics within the field. In addition, this review highlights different aspects of the MS-RCPSP, spanning the significance of performance measures, solution approaches, application areas, and the incorporation of time constraints. While project completion time, cost, and tardiness are common performance indicators, other measures such as multi-skilled staff assignment and schedule robustness are also deemed important. Although various methods have been employed to solve the MS-RCPSP including exact and approximate approaches, the selection of the most-suited approach depends on the problem’s scale, complexity, and constraints, necessitating careful consideration of each method’s strengths and weaknesses. Interestingly, several studies have jointly addressed resource and time constraints in the context of MS-RCPSP, often considering tardiness, and have proposed different algorithms, models, and metaheuristics to tackle these challenges. This paper clearly highlights research gaps and promising avenues for future research. This work provides valuable insights for project managers to effectively schedule tasks in the presence of multiple flexible resources.