Parathyroid hormone (PTH) is an important peptide hormone regulator of calcium homeostasis and osteoblast function. However, its mechanism of action in osteoblasts is poorly understood. Our previous study demonstrated that PTH activates mouse osteocalcin (Ocn) gene 2 (mOG2) promoter through the OSE1 site (Jiang et al., JBC 279, 5329–5337,2004), a recently identified ATF4-binding element. In the present study, we examine effects of PTH on ATF4 expression and activity as well as the requirement for ATF4 in the regulation of Ocn by PTH. Results show that PTH elevated levels of ATF4 mRNA and protein in a dose and time-dependent manner. This PTH regulation requires transcriptional activity, but not de novo protein synthesis. PTH also increased binding of nuclear extracts to OSE1 DNA. PTH stimulated ATF4-dependent transcriptional activity mainly through PKA with a lesser requirement for PKC and MAPK/ERK pathways. Lastly, PTH stimulation of Ocn expression was lost by siRNA down-regulation of ATF4 in MC-4 cells and in Atf4^- bone marrow stromal cells (BMSCs). Collectively, these studies for the first time demonstrate that PTH increases ATF4 expression and activity and that ATF4 is required for PTH induction of Ocn expression in osteoblasts.