Background: Aggressive behavior is an ancient and conserved trait habitual for most animals in order to eat, protect themselves, compete for mating and defend their territories. Genetic factors have been shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. Although, such types of conducts have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, selected for tameness. Results: A total of 918 up-regulated and 278 down-regulated DEG were identified. The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as the Alzheimer disease-presenilin, integrins or the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, are also up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions associated with PFC activity, are down-regulated, promoting the development of the aggressive responses selected for in Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression. Conclusions: These transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors.This analysis constitutes a first important step towards the identification of the genes and metabolic pathways that impulse aggression in cattle and, hence, we are providing a novel species as model organism for disentangling the mechanisms underlying variability in aggressive behavior.