Apolipoprotein E has long been recognized for its pleiotropic properties that together contribute to control cellular metabolism, inflammation, and pathophysiology across all organ systems. Although first recognized for its role in receptor-mediated plasma lipoprotein clearance in the liver, ApoE isoform-specific roles in modulating cellular lipid homeostasis have more recently been linked to its differential control of systemic and tissue inflammation. Beyond controlling hematopoiesis in the bone marrow as well as myeloid cell activation in the circulation and solid organs, lipid-independent properties of cellular ApoE expression are increasingly recognized to exert isoform-specific control of metabolic stress and inflammation. Its major attributes serving to control cellular metabolism include an ability for ApoE to exert a profound influence over energy metabolism. Indeed, ApoE expression is increasingly understood to control bioenergetic fuel utilization in an isoform-specific manner by modulating glycolytic metabolism and oxidative phosphorylation across a wide array of cell types that range from hematopoietic stem and progenitor cells to mature myeloid cells, adipocytes, hepatocytes, glia, neurons, and even cardiac myocytes, predisposing to a broad range of chronic and acute illnesses. While mechanisms to account for these novel forms of cellular signaling activities remain incompletely understood, a capacity for ApoE to exert isoform-specific control over genome-wide transcriptional programs is emerging. Through their ability to differentially influence cellular epigenetic imprinting, ApoE isoforms have been noted to drive both inflammatory and metabolic signaling, including via microRNA-regulated pathways that control aerobic glycolysis and fatty acid metabolism in the mitochondria. Remarkably, this form of ApoE-dependent microRNA-control of bioenergetic metabolism has recently been shown to be communicated via extracellular vesicles to recipient cells, regulating both innate and adaptive immune responses in cardiometabolic disease. Finally, emerging evidence suggests that these forms of bioenergetic signaling could account for yet incompletely understood detrimental properties that ApoE4 gene expression confers in promoting human pathology.