Targeting osteoblast may be the means of effectively improving both bone quality and mass, thus offering an intriguing alternative in the treatment of osteoporosis. Aside from injectable parathyroid hormone (PTH) and its novel preparations, PTH-related peptide (PTHrP), calcilytics, beta-adrenergic receptors, enhancement of Wnt signaling (mainly via sclerostin and Dickkopf-1 neutralization), regulation of low-density lipoprotein receptor-related protein (LPR) 5/osteoblast axis, activin, IGF-1, and bone morphogenic proteins (BMPs) are reviewed for their basic rationale and evidence of bone anabolic potential. Sclerostin neutralizing antibody, teriparatide transdermal patch, and PTHrP (1-36) are currently at an advanced stage of research. Safety and tissue specificity are the prerequisites in the development of a novel treatment, especially when addressing a chronic condition such as osteoporosis.