Background: In asthmatic children, respiratory pathogens are identified in 60%-80% of asthma exacerbations, contributing to a significant burden of illness. The role of pathogens in the clinical evolution of exacerbations is unknown. Objective: We systematically reviewed the association between the presence of pathogens and clinical outcomes in children with an asthma exacerbation. Method: PubMed, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials were searched up to October 2016 for studies reporting on respiratory pathogen exposure and clinical outcome. The Risk of Bias in Non-Randomized Studies of Interventions tool was used for quality assessment. Results: Twenty-eight observational studies (N = 4,224 children) reported on 112 different associations between exposure to any pathogen (n = 45), human rhinovirus (HRV; n = 34), atypical bacteria (n = 21), specific virus (n = 11), or bacteria (n = 1) and outcomes of exacerbation severity (n = 26), health care use (n = 38), treatment response (n = 19), and morbidity (n = 29). Restricting the analysis only to comparisons with a low to moderate risk of bias, we observed an association between HRV and higher exacerbation severity on presentation (regression p = .016) and between the presence of any pathogen and emergency department treatment failure (odds ratio [OR] = 1.57; 95% CI 1.04% to 2.37%). High-quality evidence for effect on morbidity or health care use is lacking. Conclusions: Further research on the role of pathogen-treatment interaction and outcomes is required to inform the need for point-of-care, real-time testing for pathogens. Studies with a sufficiently large sample size that address selection bias, correctly adjust for confounding, and rigorously report core patient-centred outcomes are necessary to improve knowledge.