Atherosclerotic cardiovascular disease is a chronic inflammatory disease of the blood vessels that can lead to myocardial infarction or stroke. The major cell in the atherosclerotic lesion, the macrophage, is thought to be an important contributor to the production of inflammatory mediators that exacerbate this disease. Macrophages are generally derived from circulating monocytes, which are in turn produced by hematopoietic stem and multipotential progenitor cells (HSPCs) in the bone marrow and other medullary organs. Recent studies suggest that disruption in cholesterol homeostasis or prolonged exposure to a hypercholesterolemic environment can influence HSPCs to over-produce monocytes, resulting in monocytosis. These monocytes may carry a pre-programed ability to become M1-like macrophages once they enter the atherosclerotic lesion. Future studies may help to differentiate the role of such pre-programing versus responses to local environmental cues in determining M1, M2, or other macrophage phenotypes in atherosclerotic lesions.Innate immunity has long been considered a driving force in the initiation and progression of atherosclerotic cardiovascular disease (CVD) (1). Indeed, inflammation is a process that has attracted considerable attention as a potential therapeutic target in atherosclerosis. It has also become well accepted that cholesterol metabolism is intimately linked to inflammation and innate immune processes. This close relationship is not only important in the effector cells of atherosclerotic disease such as monocytes (2) and macrophages (3) but cholesterol metabolism has also been shown to play a central role in their hematopoietic precursors (4, 5). This is important as changes in cholesterol homeostasis in the hematopoietic stem and multipotential progenitor cells (HSPCs) control the rate of production of monocytes/macrophages, and possibly have an influence on their function (4-6). Increased numbers of circulating monocytes are a predictor of cardiovascular risk (7-14) and studies in mice have shown a causal role (4-6, 15, 16). These key studies in mice have also revealed that HSPCs can mobilize from the bone marrow (BM) to extramedullary sites such as the spleen (4-6, 17), where they can also produce monocytes that contribute to atherogenesis (6). In this article, we will review these topics and also explore the hypothesis that the mechanisms contributing to monocyte production from HSPCs could also influence the type and function of lesional macrophages.