Recent studies have demonstrated that transgenic zebrafish carrying the c-MYC oncogene under the control of regulatory elements from the rag2 gene (rag2:MYC) develop B lineage leukemia in addition, and sometimes in parallel to T lineage leukemia. The B lineage reporter cd79:GFP transgene facilitates green fluorescence-based identification of tumor-bearing individuals. Comparative genomic profiling of human vs. mouse tumors (left) reveals differences between tumors resulting from human and mouse MYC isoforms, which might be due to differential protein isoforms, genetic modifier loci, or both. Comparison of the two models might provide insight into how distinct disease entities arise from superficially similar genetic lesions, provide clues to druggable genetic targets mediating MYC effects, or provide clues to relapse potential. Treatment of zebrafish carrying hMYC with dexamethasone or radiation results in induction of remission and relatively speedy relapse, providing a model for understanding relapse biology, identifying treatment induced mutations, and possible discovery of novel therapeutic strategies for relapse disease.