The agents most commonly used in combination for the management of acne include topical retinoids and antibiotics. Topical retinoids normalize desquamation of the follicular epithelium, whereas antibiotics inhibit the growth of P. acnes and the production of free fatty acids. This therapeutic combination decreases comedogenesis, bacterial growth, and inflammation, thus targeting three of the four pathogenic factors associated with acne. Efficacy and tolerance are maximized with combination therapy, and the degree of skin irritation is minimized. Furthermore, adjunctive therapy with topical retinoids and antibiotics tends to produce results more quickly than single-agent therapy. This article will examine the individual agents used in combination for acne management, and discuss the mechanisms by which they achieve efficacy. The rationale of utilizing topical retinoids with antibiotics will be highlighted, particularly in relation to improved tolerance and reduced irritation.