Next generation sequencing (NGS) has begun to dramatically change research and diagnostic approaches. Compared to conventional Sanger sequencing the price per sequenced base has dropped several 1000-fold leading to a shift of the bottleneck from sequence data generation to bioinformatic interpretation. After an introduction into the principles of NGS different research applications centered on gene regulation and expression signatures will be discussed. Next, the upcoming role in the clinics will be highlighted. The possibility of parallel sequencing of hundreds of genes up to the whole exome in targeted gene panel approaches or even whole genome sequencing has shifted the paradigm in differential diagnosis of rare skeletal disorders to a sequence first strategy. But also in seemingly common skeletal disorders the parallel sequencing of many candidate genes offers unprecedented insight into the underlying disease etiologies. In a pilot study on early onset osteoporosis we found evidence for monogenic inheritance in a significant portion of patients. With increasing numbers of sequenced patients and appropriate available databases probably also more complex oligogenic inheritance patterns can be elucidated. Given the relevance of this genetic information for personalized prognosis and treatment it is to be expected that increasingly rapid genotyping at dropping costs will become a standard tool in many fields of medicine.