Chronic obstructive pulmonary disease (COPD) and asthma represent a substantial portion of primary care practice. In adults, differentiating asthma from COPD can be difficult but is important because of the marked differences in treatment, disease progression, and outcomes between the 2 conditions. Currently, clinical COPD is often misdiagnosed or undiagnosed until late in the disease. Earlier diagnosis could markedly reduce morbidity and improve quality of life. Establishing a diagnosis of COPD requires spirometry testing, interpreted in the context of the patient's symptoms, smoking status, age, and comorbidities. Additional tests and tools may be helpful in the differential diagnosis, including questionnaires specifically developed to discriminate between COPD and asthma and, in special cases, imaging studies. Follow-up and monitoring of asthma and COPD are always necessary and provide additional benefit in patients in whom only continued care and reassessment can confirm the final diagnosis, such as younger individuals with fixed airway obstruction, smokers with asthma, and patients with both disorders. Key areas for improvement include enhanced case identification, improved quality and interpretation of findings on spirometry, and increased use of tools such as differential diagnosis questionnaires and algorithms to guide the diagnostic and monitoring process. To achieve optimal outcomes, the primary care team should make every effort to establish a firm diagnosis. For this review, we conducted a PubMed search with no time limits using the Medical Subject Headings chronic obstructive pulmonary disease or COPD and asthma, in association with the following search terms: diagnosis, differential diagnosis, mixed or comorbid disease, diagnostic techniques, spirometry, questionnaires, and primary care.