The zebrafish is an ideal vertebrate model system to investigate the complex genetic basis of cancer because it has the capacity for in vivo tumour-cell imaging and forward genetic screens, and the molecular mechanisms regulating malignancy are remarkably conserved when compared with human. Our laboratory has previously generated transgenic zebrafish models that overexpress the mouse c-Myc gene fused to enhanced green fluorescent protein (EGFP) and develop T-cell acute lymphoblastic leukaemia (T-ALL) that recapitulates the human disease both molecularly and pathologically. Our previous models have been limited by disease onset prior to sexual maturity and by the low disease penetrance when conditional transgenic embryos are injected with Cre RNA. Here, we report a novel system in which compound transgenic fish expressed both Cre controlled by the heat-shock promoter and a rag2-promoter-regulated lox-dsRED2-lox-EGFP-mMyc cassette rag2-LDL-EMyc in developing T cells. After heat-shock treatment at 3 d postfertilisation (dpf) for 45 min at 37 degrees C, 81% of compound transgenic fish developed T-lymphoblastic lymphoma (T-LBL, mean latency 120 +/- 43 (standard deviation) days of life), which rapidly progressed to T-ALL. Heat-shock-regulated transgenic technology in zebrafish provides the missing link necessary to exploit the powerful genetic capacity of this organism to probe the multi-step molecular pathogenesis of leukaemia.