Runt-related transcription factor-1 (Runx1) is well known for its functions in hematopoiesis and leukemia but recent research has focused on its role in skeletal development and osteoarthritis (OA). Deficiency of the Runx1 gene is fatal in early embryonic development, and specific knockout of Runx1 in cell lineages of cartilage and bone leads to delayed cartilage formation and impaired bone calcification. Runx1 can regulate genes including collagen type II (Col2a1) and X (Col10a1), SRY-box transcription factor 9 (Sox9), aggrecan (Acan) and matrix metalloproteinase 13 (MMP-13), and the up-regulation of Runx1 improves the homeostasis of the whole joint, even in the pathological state. Moreover, Runx1 is activated as a response to mechanical compression, but impaired in the joint with the pathological progress associated with osteoarthritis. Therefore, interpretation about the role of Runx1 could enlarge our understanding of key marker genes in the skeletal development and an increased understanding of Runx1 could be helpful to identify treatments for osteoarthritis. This review provides the most up-to-date advances in the roles and bio-mechanisms of Runx1 in healthy joints and osteoarthritis from all currently published articles and gives novel insights in therapeutic approaches to OA based on Runx1.