The key research and development steps for bioactive glass (45S5 Bioglass) are documented from the date of discovery in 1969 through FDA approvals of the first dental, ENT, maxillo-facial and orthopedic clinical products. Understanding the mechanisms and quantifying the rapid surface reactions to form a bone-bonding hydroxyl-carbonate apatite (HCA) layer on the bioactive glass in contact with living bone was a vital part of the early development of this class of biomaterials. A key later discovery was enhanced osteogenesis and in situ bone regeneration by controlled release of ionic dissolution products from the bioactive glass particulates that leads to up-regulation and activation of seven families of genes, a process called osteostimulation.