The conventional perspective of acne pathogenesis holds that Propionibacterium acnes colonizes the duct of the sebaceous follicle, causing an innate immune response and the progression from a so-called noninflammatory comedo to an inflammatory papule, pustule, or nodule. However, this viewpoint has come under increasing scrutiny over the last decade, as evidence has emerged supporting a role for inflammation at all stages of acne lesion development, perhaps subclinically even before comedo formation. The immunochemical pathways underlying the initiation and propagation of the inflammation in acne are complex and still being elucidated, but may involve Propionibacterium acnes as well as several inflammatory mediators and their target receptors, including cytokines, defensins, peptidases, sebum lipids, and neuropeptides. This review presents evidence to support the notion that acne is primarily an inflammatory disease, challenging the current nomenclature of noninflammatory versus inflammatory acne lesions and suggesting that the nomenclature is outdated and incorrect. The evidence in support of acne as an inflammatory disease also has clinical implications, in that anti-inflammatory drugs used to treat the disease can be expected to exert effects against all lesion stages, albeit via distinct mechanisms of anti-inflammation.