Over the last 25 years the molecular basis of many inherited skin diseases has been revealed. Autosomal recessive diseases, characterised by bi-allelic loss-of-function mutations, have been ideally suited to candidate gene approaches – identifying loss of key structures or proteins to reveal clues to pathogenesis. Likewise, autosomal dominant genodermatoses have been dissected using classic genetic linkage and fine mapping studies. These days, however, many of the straightforward “low hanging fruit” diseases have been picked and characterised – but new approaches, including next generation sequencing, have emerged to track down those diseases that remain unpicked on the higher branches. Notably, whole exome sequencing has resulted in a plethora of new genodermatosis gene discoveries, many of which continue to provide fascinating and original insights into skin biology. Over the last decade more than 160 genodermatoses have been elucidated at a gene level, including 35 brand new inherited diseases. Next generation sequencing also enables gene hunting to be taken to another level in being able to understand complex phenotypes and to provide clinical insight. For example, gene hunting in consanguineous families may often reveal multiple recessive gene mutations contributing to phenotype. Moreover, modern gene hunting can often establish specific diagnoses before the full features manifest, thereby allowing for a new era of pre-emptive diagnostics that improve clinical skills and allow for better prognostication and management in the clinic. Precision genetic diagnoses also impact on improving treatments. For example, several arteriovenous malformations have been shown to result from activating mutations in the RAS/MAPK pathway, leading to clinical use of drugs such as trametinib (for MAP2K1 mutations) or vemurafenib (for BRAF mutations) instead of drugs such as sirolimus. Indeed, precision diagnostics through next generation sequencing is stratifying and personalising optimal therapies. This presentation will focus on modern gene hunting approaches, presenting new diseases and recent discoveries, as well as illustrating tangible new benefits for patients.