(A) Current clinical trials involving live microbiome-based skin therapeutics are based on the paradigm of (re)introducing or increasing the abundance of commensal microbes that naturally produce molecules with bioactivity to combat growth or pathogenicity of unwanted bacteria such as S. aureus. These strains typically produce AMPs, which can directly kill bacteria, or autoinducing peptides (AIPs), which impede pathogenic behaviors by inhibiting quorum-sensing dependent expression of key virulence factors. (B) Another therapeutic approach that has recently garnered attention due to promising results in animal models, but which remains untested in humans, is using skin commensals as chassis for exogenous expression of immunogenic antigens. In mice, for example, expression of tumor antigens (purple lines) by S. epidermidis enhanced immune responses against melanoma. These could stimulate both CD4⁺ and CD8⁺ T cells through a combination of surface and secreted antigen expression. (C) Separately, recent work has identified the accumulation-associated protein (aap) on the surface of S. epidermidis as especially stimulatory towards B cell–mediated antibody responses. Mice colonized with a strain of S. epidermidis engineered to express a nonnative peptide in place of the central aap beta-helix (purple segment) generated antigen-specific antibodies sufficient to protect them against humoral immune response to tetanus toxin.