Mammalian lipid droplets - tiny lipid-filled pockets floating amidst a cell's cytoplasm - represent an intracellular first line of defense against microbial pathogens, researchers report. Previously thought to be simple cellular stores of convenient energy that may support infection, the new findings show that the structures are instrumental in organizing and supporting intracellular immune responses. These insights may help inform future antimicrobial strategies to help combat the rise of antibiotic resistance. Eukaryotic cells store energy in the form of neutral fatty acids packed into tiny organelles called lipid droplets (LDs), which reside in all cells and cell types. As rich energy sources, some LDs become physically attached to mitochondria, where the lipids they contain help fuel critical metabolic processes. However, pathogens often hijack and exploit these energy reserves during infection, providing intracellular marauders with a source of nutrients for their survival and growth. Given the ceaseless coevolutionary arms race between pathogens and a host's immune response, it stands to reason that cells may have imbued LDs with innate defense mechanisms to thwart infection. While there is limited evidence suggesting that LDs actively participate in innate defense, much remains unknown. Using liver cells in mice and a proteomic approach, Marta Bosch and colleagues evaluated the role of mammalian LDs in immune defense. When exposed to the bacterial toxin lipopolysaccharide (LPS), Bosch et al. observed that the LD proteome within the threatened cells changed - LDs grew in number and size and began to form protein complexes with known antimicrobial activity, like CAMP. What's more, activated LDs became uncoupled from mitochondria, driving a metabolic shift within the cell toward an environment more conducive to host defense. "There is great and justifiable excitement regarding the functions of LDs and other membraneless organelles and their associated phase transitions in many cellular processes," writes Douglas Green in a related Perspective. "The studies by Bosch et al. suggest that we have much to learn..."