Trichomes and cuticles are key protective epidermal specializations. This review highlights the genetic interplay existing between trichome and cuticle formation in a variety of species. Controlling trichome development, the biosynthesis of trichome-derived specialized metabolites as well as cuticle biosynthesis and deposition can be viewed as different aspects of a common defensive strategy adopted by plants to protect themselves from environmental stresses. Existence of such interplay is based on the mining of published transcriptomic data as well as on phenotypic observations in trichome or cuticle mutants where the morphology of both structures often appear to be concomitantly altered. Given the existence of several trichome developmental pathways depending on the plant species and the types of trichomes, genetic interactions between cuticle formation and trichome development are complex to decipher and not easy to generalize. Based on our review of the literature, a schematic overview of the gene network mediating this transcriptional interplay is presented for two model plant species: Arabidopsis thaliana and Solanum lycopersicum. In addition to fundamental new insights on the regulation of these processes, identifying key transcriptional switches controlling both processes could also facilitate more applied investigations aiming at improving much desired agronomical traits in plants.