Gene expression patterns and developmental mechanisms governing the outgrowth and patterning of animal appendages help us better understand and appreciate the evolution of these body parts. Small but persistent traces of RNA have previously been identified in the human hair shaft, where viable cells are no longer present. Whether RNA persists in other skin appendages is not well understood. We use nails, feathers, claws, talons, hooves, scales, and other skin appendages to construct phylogenetic trees, perform targeted chemical analysis to determine environmental exposures, and find out if RNA persists in the tissues composed of “dead” cells. Utilizing samples from a broad spectrum of species (human and other primates, mammals, amphibians, reptiles, birds, and fish), we investigate the potential of a broader use of keratinized tissues, given their accessibility and protective characteristics, for phylogeny reconstruction and RNA-based testing. The molecular analysis of keratinized tissues may open the way for non-invasive molecular testing of any natural population.