Introduction: Classically, vulnerable plaques at risk for acute coronary syndrome (ACS) have been defined by cellular architecture. However, contemporary imaging studies have shed light into new mechanisms of ACS (e.g., plaque erosion), challenging plaque rupture as the sole mechanism of disease. Furthermore, mechanisms within the vascular microenvironment that may modulate these disease phenotypes are poorly understood. Our objective was to examine differential programming of smooth muscle and macrophage cells amongst patients with stable and unstable plaques using spatial transcriptomics. Methods: Autopsy-derived coronary arteries were reviewed by an independent pathologist and segregated into stable (N=8) and unstable (defined by the presence of CD68+ cells and a large lipid core, N=8) plaques for spatial profiling. In combination with immunofluorescent histology, our approach enabled cell-specific, spatially resolved transcriptional profiling of plaques with mapping of cell populations via gene expression patterns. Results: We observed unique spatial and cell-specific transcriptional signatures for stable and unstable plaques including regional differences in the tunica intima and media. These regions differentially expressed pro-inflammatory (e.g., IFN-gamma, MHC Class II, pro-inflammatory cytokines) and pro-thrombotic signaling pathways. Cell-type-specific expression analysis using spatial deconvolution revealed heterogeneous CD68+ cell populations which shared gene signatures with endothelial, smooth muscle, and myeloid cells. Conclusion: Our results highlight cell-specific and regional pro-inflammatory and coagulation transcriptional changes within unstable coronary arterial plaques and supports the idea of cellular dedifferentiation and intra-plaque plasticity as a contributor to plaque instability. These findings may help to identify novel mediators of ACS and potential therapeutic targets.