Initiation of effective topical therapy as early as possible within the disease course is associated with improved patient experiences and better therapeutic outcomes in most dermatological diseases. Additionally, patient adherence is associated with better outcomes and lower long-term treatment costs, while poor adherence is directly linked to poor treatment results and patient dissatisfaction. Local cutaneous irritation associated with topical drug formulations has been an historical challenge to therapy initiation and adherence. Retinoids and benzoyl peroxide-essential elements of topical acne treatment-are two of the drugs most commonly associated with application-site adverse events. Novel approaches to product formulation incorporating microsphere technology may improve treatment tolerability, encourage adherence, and contribute to better long-term therapeutic outcomes. Microsphere technology eliminates the rapid delivery of high concentrations of active drug to the application site and instead facilitates controlled release of potentially irritating drugs. It is associated with improved treatment outcomes and minimal irritation. Microsphere formulations of topical tretinoin and benzoyl peroxide currently on the market have demonstrated good efficacy and tolerability and are expected to encourage adherence and long-term therapeutic benefit.