OBJECTIVES: Clinical use of next-generation sequencing(NGS) techniques has tremendously risen. This is the result of technological advancements and simultaneously decreasing sequencing costs. Although the long-awaited $1,000 genome seems near, a clear and complete overview of the costs of NGS techniques is currently missing. Moreover, it is still  unclear how NGS technologies should be used in clinical practice.  This study assesses the costs associated with three NGS technologies: Targeted gene panels(TGP), whole exome sequencing(WES), and whole genome sequencing(WGS). Additionally, a framework is constructed, balancing costs and diagnostic yield. METHODS: The total costs of TGP, WES and WGS were calculated at the Radboud university medical center. TGP, WES and WGS can be used in various diagnostic workflows in which one test could serve as a pre-test to another. A decision framework was constructed that takes into account the costs and diagnostic yields of various workflows, informing on which workflow is most favourable at what diagnostic yields.  PRELIMINARY RESULTS: The per-sample costs of TGP (€500) are two and five times lower than per-sample costs of WES (€1,000) and WGS (€2,600), respectively. Nevertheless, using it as a pre-test for WES or WGS is only cost-saving if its’ diagnostic yield exceeds 60 or 20%, respectively. Using WES as a pre-test for WGS saves costs when its’ diagnostic yield exceeds 40%.  CONCLUSIONS: This study is the first complete overview of the costs of NGS technologies. Although it is often claimed that the $1,000 genome is near, our study shows that taking into account all direct medical costs associated with NGS, the costs of WGS are still considerably higher. The per-sample costs of TGP, WES and WGS are dependent on several assumptions, such as annual throughput and coverage. To assure transferability of our results, we constructed a flexible framework in which these assumptions can be adapted.