Acne is one of the most common skin diseases worldwide and results in major health care costs and significant morbidity to severely affected individuals. However, the pathophysiology of this disorder is not well understood. Host-microbiome interactions that affect both innate and adaptive immune homeostasis appear to be a central factor in this disease, with recent observations suggesting that the composition and activities of the microbiota in acne is perturbed. Staphylococcus epidermidis and Cutibacterium acnes (C. acnes; formerly Propionibacterium acnes) are two major inhabitants of the skin that are thought to contribute to the disease but are also known to promote health by inhibiting the growth and invasion of pathogens. Because C. acnes is ubiquitous in sebaceous-rich skin, it is typically labeled as the etiological agent of acne yet it fails to fulfill all of Koch’s postulates. The outdated model of acne progression proposes that increased sebum production promotes over-proliferation of C. acnes in a plugged hair follicle, thereby driving inflammation. In contrast, growing evidence indicates that C. acnes is equally abundant in both unaffected and acne-affected follicles. Moreover, recent advances in metagenomic sequencing of the acne microbiome have revealed a diverse population structure distinct from healthy individuals, uncovering new lineage-specific virulence determinants. In this article, we review recent developments in the interactions of skin microbes with host immunity, discussing the contribution of dysbiosis to the immunobiology of acne and newly emerging skin microbiome-based therapeutics to treat acne.