The dairy industry directly impacts the socio-economic status of roughly 150 million families worldwide through its contribution to income, food security, and access to protein. One of the most challenging aspects for dairy cows is the transition between the last stage of their pregnancy into a new lactation. The ability of a cow to deal with extensive physiological changes during the late pregnancy and early postpartum periods influences the entire lactation in terms of milk yield, quality, and health status. Observational and interventional studies are key to understanding the complexity of physiological changes during this transition in dairy cows. For example, the identification of genomic regions associated with the development of hyperketonemia will enhance our ability to identify the most susceptible animals to these metabolic diseases. Supplementation of diets with rumen-protected branched-chain amino acids during early postpartum may be a functional strategy to prevent adverse effects of excessive negative energy balance. Utilization of these studies and future applied research will be crucial to ensure the sustainability of the dairy industry worldwide.