Memory is the hallmark of the adaptive immune system, and the observation that infectious diseases often lead to lifelong immunity in individuals who survive a first infection became the genesis for the development of vaccines. Immunization, which is the iatrogenic engineering of a protective memory immune response to a pathogen, became a standard part of medical care in the twentieth century, and has had an almost incalculable positive effect on human health and wellness. Vaccines to many, but by no means all, infectious diseases have been developed and are in common use. Smallpox vaccine, arguably the most effective vaccine in human history, was (and still is) delivered through disrupted epidermis in a process called scarification. Virtually all vaccines today are delivered by means of a hypodermic needle and syringe into muscle, in a process that bypasses the epidermis and dermis and their attendant innate and adaptive immune attributes. This article discusses vaccines in the context of the newly appreciated paradigm of tissue-resident memory T cells, and specifically discusses the role of these cells in skin and other epithelial interfaces with the environment in the maintenance of protective immunity.