A key question in vascular biology is how the diversity of origin of vascular mural cells, namely smooth muscle cells (SMCs) and pericytes influences vessel properties, in particular the regional propensity to vascular diseases. This review therefore first describes the role and regulation of mural cells during vascular formation, with a focus on embryonic origin. We then consider the evidence that connects heterogeneities in SMC and pericyte origins with disease. Since this idea has major implications for understanding and modelling human disease, then there is a pressing need for new model systems to investigate mural cell development and the consequences of heterogeneity. Recent advances arising from in vitro strategies for deriving mural cells from human pluripotent stem cells as well as from the zebrafish model will be discussed and the medical relevance of these discoveries will be highlighted.