Accumulating evidence suggests that cardiovascular diseases at least partly originate in the earliest phase of life. The Generation R Study is a multi-ethnic population-based prospective cohort study in Rotterdam, the Netherlands, among nearly 10,000 women and their offspring who have been followed from early pregnancy until young adulthood. Results from the Generation R Study show that maternal prepregnancy obesity, excessive gestational weight gain, low diet quality, and smoking during pregnancy are major risk factors for birth complications and offspring cardiovascular health throughout the life course. These maternal risk factors are commonly present and often cluster in families with a low socioeconomic status or from non-Dutch origin, who are already at a higher risk of offspring cardiovascular risk factors and diseases. Our findings from the original Generation R Study strongly suggest that preconception and early pregnancy are critical periods for offspring cardiovascular health. Urgent translation to targeted prevention strategies during preconception and early pregnancy is essential to reduce cardiovascular disease risk in future generations, particularly within vulnerable populations.