<p>Lipid droplets (LDs) are ubiquitous subcellular organelles playing crucial roles in lipid and energy homeostasis. They are constantly generated in the intramembrane space of the endoplasmic reticulum (ER) through unique mechanisms. Upon maturation, they bud off from the ER outer membrane into the cytosol, travel through the cytosolic microtubular network, and make contacts to most of the other subcellular organelles to perform their cellular functions. On the one hand, these organelles can grow or fuse with other smaller ones and serve as storage for extra cellular lipid products. On the other hand, when metabolic needs arise such as in nutrient deprivation or during exercises, the esterified lipids inside the LDs undergo stepwise lipolysis, e.g. basal and stimulated lipolysis, under the regulation of a set of proteins and kinases that are specifically targeted to the monolayer phospholipid membrane of the LDs. The dynamic homeostasis of their biogenesis and lipolysis is also intimately related to other cellular signaling pathways in a paracrine or endocrine manner which actively participate in the regulation of cellular homeostasis and systemic health. This review will summarize the current understanding of the underlying mechanisms mediating the biogenesis and metabolic impact of LDs in normal and disease status with a focus on their roles in propelling and sustaining chronic inflammation.</p>