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Accumulating evidence in experimental studies reinforces the idea that adequate essential fatty acids levels can act as important players for the tonic activity of the midbrain dopamine system. Providing adequate molecular signaling, these fatty acids seems to be necessary to modulate key functions such as dopamine metabolism, release and uptake, receptor affinity, redox balance, and anti-inflammatory response, as well as neurotrophin synthesis. Taken together, these actions may improve the competence of this neuronal system to maintain a suitable resilience during development and brain maturation. In this chapter the modulatory action of essential fatty acids on the midbrain dopaminergic system are revised with emphasis on the repercussion of the deficiency or supplementation of these macronutrients to homeostatic conditions that prevent dopamine cell demise during development and aging.