The implementation of diagnostic, therapeutic, and monitoring strategies precisely tailored for each individual patient is increasingly common, perhaps most notably in oncology. Such “precision medicine,” ultimately guided by a molecular taxonomy of disease, as well as detailed molecular knowledge of disease course and therapeutic response, has been articulated as a vital goal for the future of medicine.1 The unprecedented pace of scientific progress and technologies for the deep molecular interrogation of biological samples has arguably outpaced the ability to translate this data into useful patient interventions. Nevertheless, there are emerging areas in which such data has been successfully used to create, implement, and monitor therapies. In this issue, we explore the state-of-the-art in precision medicine across a wide spectrum of dermatologic disease, including nonmelanoma skin cancers, Merkel cell carcinoma, melanoma, psoriasis, inherited structural diseases, and the skin microbiome. The existence of dominant driver pathways in both melanoma and basal cell carcinoma has resulted in the rapid development of specific inhibitors of ERK2,3 and Hedgehog signaling,4,5, respectively with substantial clinical benefit. Despite the fact that such targets have not been identified for squamous cell carcinoma or Merkel cell carcinoma, intense research efforts are now aimed at identifying appropriate targets. Immunotherapies that induce checkpoint blockade against PD1 or CTLA4 signaling have shown great promise, particularly in melanoma.6,7 It is possible that this type of immunomodulation will eventually have a role in the treatment of squamous cell carcinoma and Merkel cell carcinoma. The identification of specific genetic defects in inherited disorders of basement membrane presents a different problem. Many targets are known, but the delivery of gene replacement has proven to be difficult. It is unclear which technologies are most likely to be effective and result in stable expression of components in the appropriate cell types and contexts. Molecularly targeted therapies are not limited to cancer. The advent of biologicals for the treatment of psoriasis has not only validated the targeting of numerous cytokines and their cognate receptors, but has resulted in dramatic and sustained responses.8 However, the complexity of evaluating clinical response, predicting response and managing adverse effects presents numerous challenges in the optimal assessment and management of moderate to severe psoriasis. Finally, the microbiome has emerged as an exciting new frontier of skin biology.9 The finding that bacterial diversity and composition on skin differ by location and in disease states, suggests critical roles for heretofore unappreciated skin-immune interactions and novel therapeutic approaches for inflammatory disorders. These articles are authored by leaders at the forefront of their respective fields of expertise. The diversity of dermatologic disease and the effective translation of deep biological understanding to enable effective therapy pose significant challenges; however, the enormous progress that has been made bodes well for continued future success.