Purpose of Review <p>Sterol ester mobilization from foam cell lipid droplets (LDs) involves lipase-mediated hydrolysis. This review summarizes the main lipolytic pathways, with emphasis on their potential impact on foam cell modulation through induction of liver X receptor (LXR) signaling.</p> Recent Findings <p>Recent work links foam cells to alternatively activated, low-inflammatory phenotypes and identify LXR activation as a potential driver of this state. Neutral cholesterol ester hydrolases (NCEHs) that associate with LDs have been shown to induce LXR target genes.</p> Summary <p>Beyond their central roles in lipid storage, LDs act as metabolic hubs of bioactive lipids. Enzymes that liberate sterols from LD depots can both initiate reverse cholesterol transport and promote sterol signaling. Although lipolytic signaling remains an underexplored aspect of foam cell biology, current evidence suggests that the cellular compartment where free sterols are released may influence their activity, and cytosolic NCEHs associated with LDs could play a more direct role in modulating LXR activation.</p> Graphical Abstract <p></p>