Abstract Increased accumulation of cytoplasmic lipid droplets (LDs) in host nonadipose cells is commonly observed in response to numerous infectious diseases, including bacterial, parasite, and fungal infections. LDs are lipid-enriched, dynamic organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell and stimulus regulated. Far beyond being simply a deposit of neutral lipids, LDs have come to be seen as an essential platform for various cellular processes, including metabolic regulation, cell signaling, and the immune response. LD participation in the immune response occurs as sites for compartmentalization of several immunometabolic signaling pathways, production of inflammatory lipid mediators, and regulation of antigen presentation. Infection-driven LD biogenesis is a complexly regulated process that involves innate immune receptors, transcriptional and posttranscriptional regulation, increased lipid uptake, and new lipid synthesis. Accumulating evidence demonstrates that intracellular pathogens are able to exploit LDs as an energy source, a replication site, and/or a mechanism of immune response evasion. Nevertheless, LDs can also act in favor of the host as part of the immune and inflammatory response to pathogens. Here, we review recent findings that explored the new roles of LDs in the context of host-pathogen interactions.