p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified. Methodology/Principal Findings: We evaluated osteoblast-specific deletion of p38 alpha to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38 alpha deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38 alpha did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38 alpha disruption after birth by removal of doxycycline. Deletion of p38 alpha at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months. Conclusions: Our data demonstrates that, in addition to early skeletogenesis, p38 alpha is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.