The complex metabolic networks that modulate fetal metabolic programming and putative answers given by systems biology. This picture summarizes the putative molecular mechanisms linking impaired nutrient availability during the fetal period with adult chronic diseases such as metabolic and cardiovascular disorders, including coronary heart disease, type 2 diabetes, and insulin resistance, and introduces controversial issues that are addressed in this review by systems biology approaches. The figure illustrates the concept that fetuses adapt to an impaired supply of nutrients (under- or overnutrition) by changing their physiology and metabolism, in particular by modulating the metabolic transcriptional program of target tissues. Epigenetic modifications, such as DNA methylation and covalent posttranslational histone modifications provide a molecular explanation of how these complex metabolic networks coordinately influence fetal metabolic programming. The question of whether in utero overnutrition modulates fetal metabolic programming in the same fashion as that of a maternal environment of undernutrition is introduced, and answers from systems biology are given. In fact, we postulate that a nutrient-restricted fetal environment would be more likely associated with the induction of changes in tissue structure and function, particularly in cardiovascular system, mainly regulated by growth factors. Conversely, a maternal “obesogenic” environment is more likely associated with metabolic reprogramming of glucose and lipid metabolism in the liver. Finally, two different hypotheses regarding whether fetal metabolic programming is controlled by metabolically active target tissues such as the liver, or is modulated by central neural pathways involved in appetite and energy balance regulation such as the hypothalamus are shown, and the concept of “mitochondrial programming” is introduced as operating on the modulation of metabolic function. Red arrows show how these series of hypotheses are contrasted by the combination of a complex integration of the literature knowledge and functional analysis performed by systems biology approaches. IUFGR, intrauterine fetal growth restriction; LGA, large for gestational age; Mt, mitochondrial; SGA, small for gestational age.