Based on morphological studies performed in the sixties it was clearly demonstrated that the smooth muscle cell (SMC) is the unique cell type found in medial layer of arteries (reviewed by Wissler in 1968). 1 Simultaneously, Wolinsky and Glagov (1967) 2 showed that SMCs, together with the surrounding extracellular matrix components (elastin and collagen), constitute the contractile unit of the arterial media. It was hence recognized that the SMC is a multifunctional cell; besides its role in arterial contraction, it is also responsible for extracellular matrix component production. At that time, modified SMCs including lipid-laden SMCs, were observed in human and monkey atherosclerotic plaques. It was proposed that the intimal SMCs probably derived from SMCs of the media (Wissler, 1968). 1 These seminal observations have stimulated decades of research on the role of SMCs in atherosclerosis and other vascular diseases, in particular on the property of SMCs to retain the capacity to shift from a contractile to a synthetic phenotype (for a historical review, see Campbell and Campbell, 2012). 3 This field of research has expanded considerably by uncovering the importance of, for example, embryonic origin, ectopic progenitor cell origin, arterial localization, and fate of SMCs. A wealth of information is available on the mechanisms responsible for the complex structural and functional changes that SMCs undergo in vascular diseases such as atherosclerosis, restenosis, aneurysms, hypertension, pulmonary hypertension, arterial stiffness, and vascular aging. The aim of this spotlight issue is to bring together a series of papers that gives an update on SMC phenotypic diversity (Figure 1) and highlight recent insights on the underestimated deleterious role of SMCs in several vascular diseases. This issue will also provide an update to the previous Spotlight Issue on ‘Smooth Muscle Cells and Vascular Diseases’ published 6 years ago in Cardiovascular Research, focusing on exciting novel roles of SMCs while including broader vascular research fields. Each review in this spotlight issue was written by leading basic and translational researchers from different laboratories. As guest editors of this Spotlight Issue, we particularly want to thank all the contributing authors.