PURPOSE OF REVIEW: The goal of this paper is to review state-of-the-art transcriptome profiling methods and their recent applications in the field of skeletal biology. RECENT FINDINGS: Next-generation sequencing of mRNA (RNA-seq) methods have been established and routinely used in skeletal biology research. RNA-seq has led to the identification of novel genes and transcription factors involved in skeletal development and disease, through its application in small and large animal models, as well as human tissue and cells. With the availability of advanced techniques such as single-cell RNA-seq, novel cell types in skeletal tissues are being identified. As the sequencing technologies are rapidly evolving, the exciting discoveries supported by transcriptomics will continue to emerge and improve our understanding of the biology of the skeleton.