Advances in next-generation sequencing are enabling the use of genomics in the clinical management of patients. As the clinical applications of next-generation sequencing expand, clinical validation studies are becoming increasingly important. The challenges and successes of applying these novel technologies in a clinical setting are enormous. Over the past 6 months we have been working towards the implementation of targeted gene panels to stratify cancer patients for targeted therapies and the use of comprehensive gene panels and exome sequencing for the diagnosis of complex, inherited disorders. We are evaluating sample quality from various clinical lung biopsy methods and evaluate their suitability for molecular tumor profiling. We share some of the successes of translating these technologies to diagnostics and outline the remaining challenges. These include the establishment of standardised bioinformatics pipelines for variant calling and annotation, the clinical interpretation and reporting of genomic data, data management within established health IT systems, the ethical implications of offering more comprehensive gene testing than has ever been possible before, and the dynamic relationship between research and diagnostics. We discuss some of the approaches and solutions we have considered. The increasing demand for genomics in health management is challenging current funding models for genetic testing in Australia, but the potential benefits for patients are enormous and are driving implementation of these technologies across the country. In the years to come, genetic diagnosis enabled by NGS will likely become increasingly important in the clinic.