Different environments can elicit distinct phenotypes from a single genotype, referred to as phenotypic (developmental) plasticity (Stearns, 1989; West-Eberhard, 2003). Social insects have made use of this ability to establish elaborate caste systems, while other animals and plants can modify particular traits to match their environment; such as the microcrustacean Daphnia which develops structural ‘helmets’ in response to predator cues. Studies on these and other model systems have made significant contributions toward understanding the ecological and evolutionary implications of phenotypic plasticity. However, the proximate molecular mechanisms that transmit environmental information into physiological, behavioral, and morphological changes are still largely unknown. This is a key missing feature in our understanding of development, including many processes that affect human health and well-being, such as learning, adaptive immunity, and the effects of diet and exercise. We take an integrative approach to identify the epigenetic mechanisms that regulate phenotypic plasticity, and their potential roles in ecology, evolution and human health.