Heart failure is a complex clinical syndrome, represented as an impairment in ventricular filling and myocardial blood ejection. As such, heart failure is one of the leading causes of death in the United States. With a mortality rate of 1 per 8 individuals and a prevalence of 6.2 million Americans, it has been projected that heart failure prevalence will increase by 46% by 2030. Cardiac remodeling (a general determinant of heart failure) is regulated by an extensive network of intertwined intracellular signaling pathways. The ability of signalosomes (molecular signaling complexes) to compartmentalize several cellular pathways has been recently established. These signalosome signaling complexes provide an additional level of specificity to general signaling pathways by regulating the association of upstream signals with downstream effector molecules. In cardiac myocytes, the AKAP12 (A‐kinase anchoring protein 12) scaffolds a large signalosome that orchestrates spatiotemporal signaling through stabilizing pools of phosphatases and kinases. Predominantly upon β‐AR (β₂‐adrenergic‐receptor) stimulation, the AKAP12 signalosome is recruited near the plasma membrane and binds tightly to β‐AR. Thus, one major function of AKAP12 is compartmentalizing PKA (protein kinase A) signaling near the plasma membrane. In addition, it is involved in regulating desensitization, downregulation, and recycling of β‐AR. In this review, the critical roles of AKAP12 as a scaffold protein in mediating signaling downstream GPCRs (G protein–coupled receptor) are discussed with an emphasis on its reported and potential roles in cardiovascular disease initiation and progression.