Mesenchymal stem cells (MSCs) are nonhematopoietic multipotent adult stem cells. They have been shown to have a natural tropism for many tumors types, including colorectal, and are capable of escaping host immune surveillance. MSCs are known to engraft at tumors and integrate into their architecture, potentially as carcinoma-associated fibroblasts. In contrast with other malignancies, our understanding of the interactions between colorectal cancer cells and MSCs remains limited. Considering the established importance of inflammation in the colorectal cancer primary tumor microenvironment and the role of stromal cells in this process, there is a potential wealth of information to be gleaned from further investigation of interactions between these cell populations. Epithelialmesenchymal transition is central to colorectal cancer progression and MSCs have also been implicated in this process. This review explores the current knowledge (both in vitro and in vivo) of interactions between colorectal cancer cells and MSCs. It highlights potential effects of cell source, number and ratio on outcome of in vivo studies and explores strategies to more accurately explore their role in the primary tumor microenvironment. As our understanding of the underlying molecular processes in colorectal cancer develops, elucidation of these interactions will be central to development of novel therapeutic strategies for this prevalent disease.