<p>Mesenchymal stem/stromal stem cells (MSCs) are promising therapeutic candidates in regenerative medicine and tissue engineering. MSCs have been applied in many medical conditions and their therapeutic effects, safety, and efficacy have been well established over the past few decades. However, several challenges exist when utilizing whole cells in research and the clinical settings. As a result, researchers have turned their attention to cell-free alternatives to overcome these challenges. One promising approach that can achieve the desired therapeutic effects without the need of whole-cell transplantation is the use of MSC-conditioned medium and secretome. This article gives an overview of the advantages of using cell-free strategies over cell-based strategies and the various types of cell-free alternatives available. It also critically examines the various cell-free approaches in MSC research and therapy and provides an in-depth discussion on the opportunities and challenges of using these strategies, with an emphasis on recent advances in the field.</p>