A large body of research has emerged over the last decade examining empirical models of general and specific psychopathology, which take into account comorbidity among psychiatric disorders and enable investigation of risk and protective factors that are common across disorders. This systematic review presents findings from studies of empirical models of psychopathology and transdiagnostic risk and protective factors for psychopathology among young people (10–24 years). PsycInfo, Medline and EMBASE were searched from inception to November 2020, and 41 studies were identified that examined at least one risk or protective factor in relation to broad, empirically derived, psychopathology outcomes. Results revealed several biological (executive functioning deficits, earlier pubertal timing, genetic risk for ADHD and schizophrenia, reduced gray matter volume), socio-environmental (stressful life events, maternal depression) and psychological (low effortful control, high neuroticism, negative affectivity) transdiagnostic risk factors for broad psychopathology outcomes, including general psychopathology, internalising and externalising. Methodological complexities are discussed and recommendations for future studies of empirical models of psychopathology are presented. These results contribute to a growing body of support for transdiagnostic approaches to prevention and intervention for psychiatric disorders and highlight several promising avenues for future research. •First systematic review of empirical models of psychopathology and risk and protective factors.•Biological: executive functioning deficits, earlier pubertal timing, genetic risk, gray matter volume.•Socio-environmental: stressful life events, maternal depression.•Psychological: Low effortful control, high neuroticism/negative affectivity.•More multidisciplinary, longitudinal, causally driven research needed.