The insistence on sameness (IS) commonly exhibited by individuals with autism spectrum disorder (ASD) represents a disabling feature that is only minimally affected by current treatments. Its underlying biology is not well understood, but multiple lines of evidence implicate serotonergic (5HT) alterations and frontostriatal dysfunctions. Still, efforts to develop improved and more individualized therapeutic approaches for IS have been constrained by a lack of knowledge about mechanisms bridging genetic alterations to neural system and behavioral aspects. The proposed talks aim to A) characterize the molecular, biochemical, neural system and cognitive bases of IS, and B) integrate knowledge across these levels of analysis to propose directions for future research on the etiology and treatment of these behaviors. This panel will examine 1) gene networks related to IS, 2) rare genetic variants associated with hyperserotonemia (i.e., elevated levels of platelet 5HT) and repetitive behaviors, 3) rodent behavioral pharmacology studies that utilize in vivo brain measurements of 5HT, and 4) clinical studies of neurocognitive and brain system abnormalities associated with IS. We will also discuss some of the challenges inherent in integrating these types of translational efforts and in generating biomarkers and outcome measures for clinical intervention research.