The preschool age (3–6 years) is a unique period for development as both emotion regulation and foundational brain development are rapidly maturing. Emotions such as frustration are common during this age; however, there is extensive variability along the spectrum from typical to atypical. This juxtaposition of normative misbehaviors with stable irritable temperament presents unique challenges to the differentiation of normative variation from the onset of clinical problems. As such, recent research has focused efforts on improving methods for differentiating normative and clinically concerning behavior. Improved neuroimaging tools, in combination with behavioral and clinical assessment, have provided an additional tool for assessing pediatric irritability. The authors believe that joint consideration of brain–behavior atypicalities will enhance early identification of clinically concerning irritability. To this end, this chapter aims to summarize the rapid development occurring during the preschool years, describe advancements in developmentally appropriate irritability assessments, and integrate these measurements within a neurodevelopmental framework.