In their most typical forms, asthma and chronic obstructive pulmonary disease (COPD) are clearly distinguishable, but many patients with chronic airflow limitation demonstrate features of both conditions and have worse health outcomes than those with either disease alone. This has been called the asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS), but as yet, it lacks a precise definition. However, given the different pathways by which a patient can come to demonstrate features of both asthma and COPD, ACOS is not thought to represent a single disease but to include several heterogeneous phenotypes with different underlying mechanisms. These issues have important implications for guidelines because some existing treatment recommendations for asthma and COPD are in conflict, and patients with both asthma and COPD have specifically been excluded from major pharmacologic trials. As a result, there is little evidence at present to support specific treatment recommendations for ACOS on the basis of efficacy or effectiveness, yet these patients continue to present for diagnosis and management, mainly in primary care. This article highlights the need for clinical guidance about ACOS, summarizes recommendations about its diagnosis and treatment from a sample of national asthma and COPD guidelines, and proposes a way forward, as suggested in a collaborative Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease report, to provide health professionals with interim recommendations about syndromic recognition and initial treatment based on both potential effectiveness and potential risk. Additional research in broad populations is urgently needed to develop a precise definition for ACOS, characterize its phenotypes, and identify opportunities for targeted treatment.