Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by hyperactivity, inattention, and impulsive behaviors and has significant societal impact. ADHD is recognized as a heterogeneous disease, and genetic and/or environmental factors underlying pathogenesis remain largely unknown. There is an obvious need to increase knowledge on molecular signaling and brain pathways underlying disease development, and genetic mouse models are key to this goal. In this issue of EMBO Molecular Medicine, D'Andrea et al (2015) combine state-of-the-art genetic and behavioral approaches in the mouse to demonstrate an essential role for PI3Kγ and cAMP homeostasis in ADHD-related behaviors, through signaling mechanisms operating at the level of the locus coeruleus, the main source of noradrenaline in the brain. Furthermore, the study posits PI3Kγ knockout mice as a novel tool of high interest for modeling ADHD endophenotypes.