Background: Cutibacterium acnes has been identified as one of the main triggers of acne. However, increasing knowledge of the human skin microbiome raises questions about the role of other skin commensals, such as Staphylococcus epidermidis, in the physiopathology of this skin disease. Summary: This review provides an overview of current knowledge of the potential role of S. epidermidis in the physiopathology of acne. Recent research indicates that acne might be the result of an unbalanced equilibrium between C. acnes and S. epidermidis, according to dedicated interactions. Current treatments act on C. acnes only. Other treatment options may be considered, such as probiotics derived from S. epidermidis to restore the naturally balanced microbiota or through targeting the regulation of the host’s AMP mediators. Key Messages: Research seems to confirm the beneficial role of S. epidermidis in acne by limiting C. acnes over-colonisation and inflammation.