A hypothesis that is currently in vogue in the field of carcinogenesis suggests that a small, but identifiable population of cells within a tumor provides the “selfrenewal” phenotype of cancer. An extension of this hypothesis is that these self-renewing cells (cancer stem cells) most closely resemble the cell of origin for a given cancer (Reya et al. 2001). Based on this hypothesis, the originating cell of a cancer is increasingly believed to be a primitive cell with the ability to undergo division with high-phenocopy fidelity and retention of multipotency. This intersecting path between developmental biology and cancer is comfortable terrain for those involved in the study of childhood malignancies, particularly sarcomas and lymphoid cancers. The oncogenic events associated with sarcomagenesis and leukemogenesis are in many cases understood and characterized by pathognomonic translocations occurring within identifiable cell lineages (Crans and Sakamoto 2001; Mackall et al. 2002; Helman and Meltzer 2003). This understanding has led to the development and study of several highly relevant animal models of sarcoma and leukemia. Recent technological advances have encouraged extensive interdisciplinary and cross-species analyses of animal models from flies to mice to dogs to humans. These models serve not only in their historical capacity to test hypotheses emerging from the study of human cancer, but to generate new hypotheses that may be overlooked in the study of the human condition alone. This approach is well illustrated in this issue of Genes & Development by Zon and colleagues (Langenau et al. 2007), who describe the first zebrafish model of rhabdomyosarcoma (RMS), a pediatric malignancy thought to arise from skeletal muscle. Through zebrafish, Langenau et al.(2007) identify an important oncogenic pathway that characterizes a subset of RMS patients as well as a viable candidate for a RMS cell of origin.