The tumor microenvironment contains numerous cellular elements, such as cancer-associated fibroblasts (CAF) and activated myofibroblasts that participate in fibrovascular, vascular, and chemo/cytokine support of tumors. Using bone marrow transplant recipient mice harboring CD44 knockout (KO) mesenchymal stem cells (MSC), the precursor population for CAFs and myofibroblasts, Spaeth and colleagues observed the inability of engrafted CD44-KO stromal cells to provide tumor support, to generate vascular support, and importantly, to transition from the benign MSC phenotype to the tumor-supportive aggressive myofibroblast phenotype. The spectrally unmixed image displays smooth muscle actin + CAFs and myofibroblasts (red) from bone marrow derived CD44-KO (green) MSC in the tumor microenvironment. For details, see article by Spaeth and colleagues on page 5347.