Adipose tissue can be regarded as a multidepot organ responsible for metabolic homeostasis by managing sophisticated energy transactions as well as by producing bioactive molecules that regulate insulin sensitivity and immune and vascular responses. Chronic nutrient excess expands adipose tissue, and concomitant variations in its cellular and matrix remodeling can affect the extent of the metabolic dysfunction that is associated with obesity. Preadipocytes, also termed adipose progenitor cells, play a pivotal role in determining whether a dysfunctional hypertrophic state arises as opposed to a hyperplastic process in which mature adipocytes remain relatively responsive. Obesity is associated with infiltration of macrophages, and these immune cells have been shown to communicate with preadipocytes to influence how they differentiate, survive, and proliferate. Understanding macrophage-preadipocyte interactions and their effect on adipose remodeling mechanisms may identify potential therapeutic molecular targets to improve adipose tissue function, even in the face of obesity. Adv. Nutr. 4: 67-75, 2013.