A systems-level understanding of the immunomodulatory, regenerative, and pro-/antifibrosis functions of mesenchymal stromal cells (MSCs) is crucial for their therapeutic development. Given the complexity of MSCs and their interactions within the microenvironment, a systems biology approach is essential to achieve practical objectives such as identifying targets, developing combination therapies, and improving clinical strategies while avoiding adverse effects. This study addresses this need by developing a molecular systems architecture of the MSC microenvironment, which organizes the complex biomolecular interactions between MSCs and other cells. This architecture provides a visual map of MSC interactions, identifies key crosstalk, reveals potential therapeutic targets, and establishes a framework for creating future predictive, quantitative computational (in silico) models. The ultimate goal is to facilitate the development of more effective combination therapeutics and clinical strategies, and this work—beginning with the molecular systems architecture—is the foundational step toward that end