The transition period, from 3 wk before to 3 wk after parturition, is critically important to health, production, and profitability of dairy cows. Most health disorders occur during this time. Compared with other stages of the lactation cycle, relatively little is known about fundamental biological processes during the transition period. The regulation and coordination of lipid metabolism among adipose tissue, liver, gut, and mammary gland are key components of the adaptations to lactation. Lipid accumulation in liver may contribute to health disorders and decreased milk production. Knowledge of key control points in hepatic metabolism of long-chain fatty acids is lacking, as is an understanding of the metabolic effects of hormones, growth factors, and cytokines that mediate stress. Recent evidence indicates that supplemental fats or restricted intakes before parturition can induce a coordinated set of metabolic changes in metabolism of long-chain fatty acids, including peroxisomal beta-oxidation, perhaps mediated by peroxisome proliferator-activated receptors. Estimates of the mixture of fuels constituting metabolizable energy in cows during the early postpartum period suggest that supply of amino acids and glucogenic compounds may be under proposed optima, whereas ketogenic and lipogenic compounds and long-chain fatty acids may be in excess. Because dietary fat does not suppress body lipid mobilization, during the early postpartum period supplemental fat may further imbalance the mixture of fuels and lead to decreased dry matter intake. Increased understanding of the biology of the transition period should decrease health problems and increase profitability of dairy cows.