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Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.