Cardiac macrophages play a crucial role in the development and progression of cardiovascular diseases, including myocardial infarction, cardiac hypertrophy, and myocarditis. Macrophages are plastic cells that change their polarization states and functions in response to alterations in the surrounding environment. This process is deeply involved in various biological processes such as inflammation, tissue remodeling and repairing, exacerbating or mitigating the diseases progression. Thus, macrophages have emerged as potential therapeutic targets for multiple cardiac diseases. Upon sympathetic activation, adrenergic/ cyclic adenosine monophosphate (cAMP) signaling axis markedly modulates macrophages polarization and functions. It has been well-established that the intracellular cAMP is highly compartmentalized in cardiomyocytes. However, the spatiotemporal regulation of cAMP in cardiac macrophages and its implications in macrophage-driven cardiac diseases remain to be elucidated. In this review, we focus on the adrenergic/cAMP regulation of macrophage plasticity and function in the heart and discuss potentials and challenges of targeting the adrenergic/cAMP axis for cardiac diseases.