RAS family members are among the most frequently mutated oncogenes in human cancers. Given the utility of zebrafish in both chemical and genetic screens, developing RAS-induced cancer models will make large-scale screens possible to understand further the molecular mechanisms underlying malignancy. We developed a heat shock-inducible Cre/Lox-mediated transgenic approach in which activated human kRASG12D can be conditionally induced within transgenic animals by heat shock treatment. Specifically, double transgenic fish Tg(B-actin-LoxP-EGFP-LoxP-kRASG12D; hsp70-Cre) developed four types of tumors and hyperplasia after heat shock of whole zebrafish embryos, including rhabdomyosarcoma, myeloproliferative disorder, intestinal hyperplasia, and malignant peripheral nerve sheath tumor. Using ex vivo heat shock and transplantation of whole kidney marrow cells from double transgenic animals, we were able to generate specifically kRASG12D-induced myeloproliferative disorder in recipient fish. This heat shock-inducible recombination approach allowed for the generation of multiple types of RAS-induced tumors and hyperplasia without characterizing tissue-specific promoters. Moreover, these tumors and hyperplasia closely resemble human diseases at both the morphologic and molecular levels.myeloproliferative disorder ͉ RAS ͉ rhabdomyosarcoma ͉ intestine ͉ malignant peripheral nerve sheath tumor R AS genes encode a family of 21-kDa proteins that switch between inactive GDP-bound (RAS-GDP) and active GTPbound (RAS-GTP) conformations. Once in its activated GTPbound form, RAS interacts with downstream effectors to modulate diverse cellular responses, including proliferation, differentiation, and survival (1). Point mutations within RAS family members often occur at codon 12, 13, or 61 (2), which abolish RAS-GTP hydrolysis and lead to constitutive activation of downstream signaling pathways. These activating mutations are common in human malignancies; for example, Ͼ90% of pancreatic adenocarcinomas, 50% of colorectal cancers, 25-50% of lung cancers, 5-35% of rhabdomyosarcomas (RMS), and 25-50% of myeloid leukemia have mutational activation of RAS family members. Among the three different human RAS genes (H-, N-,