An increasing amount of clinical and epidemiological data support the hypothesis that early life nutritional is an important factor that influences the trajectory of life-long mental health and risk of neurobehavioral diseases, a concept known as the Developmental Origins of Health and Disease (DOHaD). The cost to society of early life nutritional deficiencies on the brain stems from the failure to reach full neurobehavioral potential, which results in loss of educational and job potential and that has societal and economic consequences. Preclinical models support the DOHaD concept and provide the biological underpinnings of this effect as it relates to mental health. This lecture discusses what is known about these fundamental biological mechanisms. Some of the nutrients for which there is evidence of long-term effects play a role in fundamental brain metabolic processes that are critical for normal construction of the brain in the first 1000 days. The brain and behavioral deficits in adulthood following early life deficiencies relate directly to permanently alter regional brain architecture, suggesting that critical periods of brain structural development are present and nutrient-sensitive. Failure to construct the brain normally in these critical periods results in permanent structural alterations not only to the primary regions affected by the nutrient deficiency, but also to extended neural circuits that depend on the integrity of the primary areas. In addition, some nutrients associated with long-term neurobehavioral effects induce epigenetic modifications in genes that are critical for neurologic function. Preclinical models show that these modifications found acutely during the period of nutrient deficiency persist into adulthood, thereby providing a plausible mechanism for the long-term loss of synaptic plasticity. The two mechanisms are not mutually exclusive and likely work in concert to produce the long-term effects.