Despite their importance in fibrosis, the origin of fibroblasts and the genesis of the various subpopulations characterized by distinct phenotypes remain unclear. Various studies have described distinct and relatively stable phenotypes in fibroblasts isolated from lung tissue undergoing remodeling, which were not present in the normal intact tissue. This indicates a process by which these distinct fibroblast subpopulations could arise de novo from resident lung progenitors or precursor cells and/or be recruited from distal organs, such as the bone marrow. Evidence for these possibilities is reviewed, but there is as yet incomplete understanding of the precise precursor cells and the potential interrelationships between the various phenotypes, especially as to how they relate to the distinct myofibroblast phenotype. Moreover, the complexity of the mechanism for the genesis of these phenotypes, such as the myofibroblast, is highlighted by the multilevel regulation of the differentiation process, with evidence for the importance of multiple signaling pathways, transcription factors, and epigenetic mechanisms. Future studies into these various unsettled areas are essential to provide further insights that may help provide the pathway for novel translational approaches.