This report proposes that hyperketonaemia in early lactation (formerly known as primary ketosis) is associated with fatty liver or hepatic lipidosis and is a ‘hub’ for health risks, such as oxidative stress and inflammation, immunosuppression and infectious diseases. Cows reduce their dry matter intake (DMI) antepartum and DMI only slowly increases postpartum compared with the rapid rise in milk production, leading to undernutrition, mainly a deficit of energy. The resulting negative energy balance (NEB) is genetically correlated with milk yield (MY) and leads to a mobilisation of reserves from adipose tissue for up to 2 months or even longer. The non-esterified fatty acids (NEFA) released by this mobilisation are used for milk production and energy metabolism, but exceed requirements and initiate a rapid increase in NEFA concentration postpartum, eventually triggering ectopic deposition in the muscles and liver. The uptake of NEFA by the liver is mediated by the fatty acid transporter CD36, and the NEFA are metabolised for ATP production and at incomplete oxidation, for ketogenesis as β-hydroxybutyric acid, which can lead to hyperketonaemia. NEFA uptake very often exceeds liver metabolism. The surplus is shifted to resynthesis of triglyceride (TG), which can be exported as very-low-density lipoproteins (VLDL) across the basolateral membrane. VLDL extrusion is limited in ruminants and hence TG accumulate in the liver, leading to hepatic lipidosis. Hepatic lipidosis causes impairment of morphology and hinders certain functions of the liver, resulting in leakage of enzymes, reduced gluconeogenesis, ureagenesis and triggering oxidative stress and inflammation of the liver. The metabolism during the transition period is regulated by homeorhesis to prioritise the support the physiological state of milk production. However, at high MY, homeorhesis with an uncoupled growth hormone–insulin-like growth factor-1 axis and insufficient DMI predisposes to a pronounced NEB and a consequent hepatic lipidosis.