Culling for infertility remains the main reason for disposal of dairy cows, limiting productive lifespan. In extreme cases, ovulation is inhibited, preventing the possibility of conception. More often cows do conceive, but fail to remain pregnant owing to intrinsic problems in the embryo and/or to a poor-quality reproductive tract environment. Both aspects have a genetic component and are also influenced by management practices affecting nutrition and health. The relative importance of these factors varies among heifers, first-lactation and older cows. A common theme, however, is that an internal signalling system exists which reduces fertility when the cow is in an unsuitable metabolic state to sustain a pregnancy. This may be directly related to nutrient shortage caused by inadequate feed intake, or because available nutrients are being prioritized towards growth or milk production, away from reproduction. Evidence is presented for the involvement of the somatotrophic axis (GH, IGF1, insulin, IGFBP2) and leptin as key metabolic signalling molecules. Another emerging theme is the interaction between metabolism and disease that affects the fertility. Common examples include (i) calf diseases causing inadequate heifer growth and increased age at first calving; (ii) poor peripartum energy status reducing the capacity of the uterus to involute and mount an effective immune response, thereby increasing the likelihood of endometritis; and (iii) development of mastitis after conception, a contributory factor to both early and late embryo mortality. Finally, recent evidence suggests that times of metabolic stress cause mitochondrial damage that also contributes to a reduction in longevity.