Parathormone (PTH)-related protein (PTHrP), a widespread factor in mammalian tissues, is envisioned as a string of cytokines, due to the complex autocrine/paracrine/intracrine actions of its different domains. Alternative splicing of PTHrP gene transcripts and processing of their translation products generate various fragments with different activities. In both fetal and adult skeleton, PTHrP is now considered as an important modulator of bone remodelling. Its N-terminal fragment exhibits structural homology to the N-terminal domain of PTH and interacts with the PTH type 1 receptor (PTH1R) in osteoblasts. Intermittent administration of this PTHrP fragment induces bone anabolic effects. In addition, PTHrP domains other than its N-terminal domain seem to have important yet poorly defined roles in bone metabolism. Thus, C-terminal PTHrP (107-139) -or just its 107-111 epitope- can prevent osteoclast activation, and it also interacts with osteoblastic cells via a PTH1R-unrelated receptor. Transient exposure of human osteoblastic cells to either PTHrP (107-139) or PTHrP (1-36) similarly induced cell differentiation and promoted cell viability. Moreover, both peptides accelerated the impaired bone regeneration after marrow ablation in diabetic or glucocorticoid-treated mice. These PTHrP peptides also rapidly induced the expression of vascular endothelial growth factor (VEGF), an angiogenic factor with an important role in bone formation, in human osteoblastic cells. Of interest, however, PTHrP (107-139), in contrast to PTHrP (1-36), was shown to interact with the VEGF receptor 2 to modulate the aforementioned osteogenic effects. Current findings strongly suggest that C-terminal PTHrP exerts potential anabolic effects in part through the VEGF system in osteoblasts.