Studies in recent years have resulted in rapid progress in the reprogramming of terminally differentiated somatic cells toward their embryonic and pluripotent states. These discoveries not only allowed the understanding of the unique "stemness" feature of stem cells, but also have been advantageous in bypassing the difficult ethical debates on applying embryonic stem cells in biomedical research and regenerative medicine. However, most of the strategies to date have relied on ectopic expression of a particular set of transcription factors by integrating viruses, potentially leading to unexpected mutations and tumorigenesis that restrict their clinical applications. A few years ago, germ cells were also reported to have the potential to become pluripotent after treatment with extrinsic growth factors in cell culture, without the risk of mutations in their therapeutic use. The understanding of the germ cell differentiation pathway will have significant implications on stem cell biology. For over a decade, Drosophila germ cells have emerged as a powerful system used to study both the extrinsic and intrinsic factors in a microenvironmental "niche" for stem cell self‑renewal and differentiation. In addition, other adult fly stem cell lineages that mimic human intestinal and haematopoietic stem cells were also identified recently. Because of their powerful genetics and relatively short lifespan, we anticipate discoveries from flies will provide valuable knowledge to unravel the mysteries of stem cells in the coming years.