Despite major advances in our understanding of transition and early lactation cow physiology and the use of advanced dietary, medical, and management tools, at least half of early lactation cows are reported to develop disease and 57% of cow deaths occur during the first week of lactation. Excessive lipolysis (measured as plasma FFA) is a major risk factor for the development of displaced abomasum, ketosis, fatty liver, and metritis, and may also lead to poor lactation performance. Lipolysis triggers adipose tissue (AT) remodeling that is characterized by enhanced humoral and cell mediated inflammatory responses, and changes in its cellular populations distribution and extracellular matrix composition. Uncontrolled AT inflammation perpetuates lipolysis as we have observed in cows with displaced abomasum. Efficient transition cow management ensures a moderate rate of lipolysis that is rapidly reduced as lactation progresses. Adequate formulation of pre- and postpartum diet reduces AT lipolysis intensity. Additionally, supplementation with niacin, monensin, and rumen-protected methyl donors (choline and methionine) during the transition period are reported to minimize FFA release into systemic circulation. Feeding saturated FA and other energy dense compounds during early lactation improves energy balance and increases insulin concentration that limit AT lipolytic responses. Independently of the type of intervention used to modulate lipolysis around parturition and early lactation, its benefits on immune function are well documented. In general, cows with moderated postpartum lipolysis exhibit improved immune response. For example, these animals have effective PMN phagocytic activity and adequate proliferation of mitogen stimulated PBMC compared with cows with high lipolysis. To further improve the modulation of AT lipolysis and remodeling, it is necessary to identify novel biomarkers of AT function as prepartum plasma FFA and BHB lack specificity and are retrospective in nature. Understanding the inherent characteristics of AT biology in transition and early lactation cows will reduce disease incidence and improve lactation performance.