Atherosclerosis and cancer evolve through complex interactions among genetic alterations, epigenetic regulation, immune activation, and tissue microenvironmental pressure. Although their clinical manifestations differ, both diseases display somatic evolution, clonal cell expansion, altered cell identity, metabolic adaptation, and persistent inflammatory signaling. This Special Issue will focus on the shared molecular architecture that drives disease initiation and progression across atherosclerotic plaques and tumors. Particular attention will be given to genomic instability, DNA damage and repair, vascular smooth muscle cell plasticity, cancer cell-state transitions, chromatin remodeling, RNA modification, trained immunity, and clonal hematopoiesis. Studies using single-cell sequencing, spatial multi-omics, lineage tracing, liquid biopsy, and experimental disease models are especially encouraged. We also invite work examining how common pathways may produce distinct outcomes in vascular and malignant tissues, and how therapies developed in one field may be repositioned in the other. The goal is to connect cardiovascular genomics and cancer epigenetics through a unified framework of somatic evolution, immune memory, and microenvironmental selection.