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Almost 200 years of histological and molecular analysis has established that functional shifts in vascular cell populations are associated with healthy vascular function and the progression of vascular disease. Now, new methods in single-cell analysis are serving to dramatically accelerate the study of vascular cell heterogeneity. Here, we will outline the experimental and computational technologies that have made high-throughput analysis of single cells possible, and review recent studies applying these approaches to vascular cells and tissues. In particular, the application of single-cell or single-nucleus RNA sequencing has identified rare and disease-specific cell populations, drivers of cellular heterogeneity, and specific vascular disease-relevant cell populations. High-throughput approaches linking CRISPR (clustered regularly interspaced short palindromic repeats) perturbations to single-cell RNA sequencing data are providing new insights into cell type-specific mechanisms of disease, and connecting human genetic data to these mechanisms. Other single-cell approaches are providing insights into regulatory mechanisms by linking chromatin accessibility to transcription in single cells and revealing the spatial positioning of rare cell types in vascular tissues. With a variety of well-established methods and the continued development of new technologies, single-cell approaches are becoming indispensable and powerful avenues for discovering and detailing new mechanisms of vascular disease.