Theoretical and methodological research on threat conditioning provides important neuroscience-informed approaches to studying fear and anxiety. The threat conditioning framework is at the vanguard of physiological and neurobiological research into core mechanistic symptoms of anxiety-related psychopathology, providing detailed models of neural circuitry underlying variability in clinically relevant behaviors (e.g., decreased extinction, heightened generalization) and heterogeneity in clinical anxiety presentations. Despite the strengths of this approach in explaining symptom and syndromal heterogeneity, the vast majority of psychopathology-oriented threat conditioning work has been conducted using Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic categories, which fail to capture the symptom-level resolution that is afforded by threat conditioning indices. Furthermore, relations between fine-grained neurobehavioral measures of threat conditioning and anxiety traits and symptoms are substantially attenuated by within-category heterogeneity, arbitrary boundaries, and inherent comorbidity in the DSM approach. Conversely, the Hierarchical Taxonomy of Psychopathology (HiTOP) is a promising approach for modeling anxiety symptoms relevant to threat conditioning work and for relating threat conditioning to broader anxiety-related constructs. To date, HiTOP has had a minimal impact on the threat conditioning field. Here, we propose that combining the HiTOP and neurobehavioral threat conditioning approaches is an important next step in studying anxiety-related pathology. We provide a brief review of prominent DSM critiques and how they affect threat conditioning studies and review relevant research and suggest solutions and recommendations that flow from the HiTOP perspective. Our hope is that this effort serves as both an inflection point and practical primer for HiTOP-aligned threat conditioning research that benefits both fields. (PsycInfo Database Record (c) 2024 APA, all rights reserved).