Adverse exposures in utero have long been linked with an increased susceptibility to adult cardio-renal and metabolic diseases. Clear gender differences exist, whereby growth-restricted females, although exhibiting some phenotypic modifications, are often protected from overt disease outcomes. One of the greatest physiological challenges facing the female gender, however, is that of pregnancy; yet little research has focused on the outcomes associated with this, as a potential 'second-hit' for those who were small at birth. We review the limited evidence suggesting that pregnancy may unmask cardio-renal and metabolic disease states and the consequences for long-term maternal health in females who were born small. Additionally, a growing area of research in this programming field is in the transgenerational transmission of low birth weight and disease susceptibility. Pathways for transmission might include an abnormal adaptation to pregnancy by the growth-restricted mother and/or inheritance via the parental germline. Strategies to optimise the pregnancy environment and/or prevent the consequences of inheritance of programmed deficits and dysfunction are of critical importance for future generations.