The primordial HPA axis (left) may have developed first in the integument for the regulation of its defensive activity against the hostile environment and pathogens. At its center are the CRF-related peptide(s) that through CRF1 (an integrating receptor) coordinate innate immune activity and protective barrier formation directly or indirectly via the expression of the proinflammatory cytokines IL-1, IL-6, and TNF-α. An inhibitory feedback loop begins with CRF1-activated POMC-derived ACTH production/secretion and culminates with production/secretion of cortisol or corticosterone (COR) that “shuts off” HPA axis activity and inhibits the antimicrobial and protective functions of the skin barrier. The intermediate signaling molecules (POMC peptides) can both weaken the skin protective barrier via their immunosuppressive action, and strengthen it through stimulation of melanogenesis or direct antimicrobial effects. Thus, the antimicrobial and protective barrier functions were regulated and fine-tuned by the primordial HPA, because of the close association of all of its elements. During evolution, the main signaling elements of the primordial HPA axis (CRF→CRF1→POMC→ACTH→cortisol or corticosterone) may have been adapted and perfected by the central neuroendocrine system to form the HPA axis (right panel), which has separated in space and overall function from the immune system and skin. The immune system retains its stimulatory activity via cytokines. However, as Aberg et al. show in this issue of the JCI, the skin antimicrobial protective barrier is weakened by psychological stress–induced production of systemic corticosteroids (7), an unintended side effect. In this context, the cutaneous HPA axis has only low local activity and serves as an evolutionary record of the parental system.