Macrophages represent one of the most numerous and diverse leukocyte types in the body. Furthermore, they are important regulators and promoters of many cardiovascular disease programs. Their functions range from sensing pathogens to digesting cell debris, modulating inflammation, and producing key cytokines and other regulatory factors throughout the body. Macrophage research has undergone a renaissance in recent years, which has propelled a newfound interest in their heterogeneity as well as a new understanding of ontological differences in their development. In addition, recent technological advances such as single-cell mass-cytometry by time-of-flight have enabled phenotype and functional analyses of individual immune myeloid cells, including macrophages, at unprecedented resolution. In this Part 1 of a 4-part review series covering the macrophage in cardiovascular disease, we focus on the basic principles of macrophage development, heterogeneity, phenotype, tissue-specific differentiation, and functionality as a basis to understand their role in cardiovascular disease.