Aspirin-exacerbated respiratory disease (AERD) is a progressive inflammatory condition defined clinically by a triad of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and sensitivity to aspirin and other COX-1 inhibiting nonsteroidal anti-inflammatory drugs (NSAID). These patients have a characteristic reaction following aspirin or NSAID ingestion, with systemic symptoms involving multiple organ systems, including the upper and lower airways. Patients with AERD are among those with the most severe sinopulmonary inflammation, often refractory to standard treatments. Yet, there have recently been significant advances in the management of both asthma and nasal polyposis, allowing for new treatment options and a shift in standard management algorithms. However, the increased recognition and prudent use of emerging therapies, such as aspirin desensitization and biologic therapies, offer hope for improved patient outcomes and disease control. This article reviews the underlying pathophysiology and stepwise medical and surgical management in what is considered a difficult-to-treat disease.