The skin is often the first line of defense against external threats, thus, a variety of mechanisms to fortify its barrier are necessary. Three such mechanisms include cutaneous immunity, sebaceous glands, and skin microbiota. These mechanisms have evolved throughout evolutionary history to provide a stable, effective cutaneous barrier in our current environment. However, the current dogma of natural selection would not allow for rapid, species-wide change to acute alterations in the environment. In the described work, we interrogated each of the above defense mechanisms and their interface, and in the process, discovered a novel way for environmental adaptation to occur, challenging the accepted dogma of natural selection. First, we isolated murine and human sebaceous glands in vivo to characterize the homeostatic sebocyte transcriptome, with the goal to allow for better identification of sebaceous gland regulatory pathways. Related to sebaceous gland regulation, we investigated the mechanism by which T cells stimulate sebum secretion, finding that T cells secrete type 2 cytokines locally to upregulate holocrine secretion of sebum. Altering the cutaneous ecosystem has impacts on the skin microbiota, leading to our next study, where we interrogated the wound microbiota communities of a cohort of cutaneous leishmaniasis patients. These wounds frequently had pathogenic dominance of Staphylococcus aureus, leading to altered downstream immune activation and healing outcomes. Lastly, synthesizing these systems, we hypothesized that the cutaneous immune-sebum circuit exists to reciprocally regulate the skin microbiota at homeostasis. In this study, we found that shifts in the microbiome and immune system do not acutely affect sebum secretion, but alter gametic small, noncoding RNA abundance, allowing for persistence of phenotypes transgenerationally. This novel phenomenon for introducing microbial- and immune-dependent phenotypic diversity in successive generations in response to environmental alterations may be termed “host-microbe inheritance.” This discovery indicates the possibility of an alternative route to adaptation on a shorter timescale than natural selection, a much-needed mechanism in the face modern, man-made environmental change.