Cell transplantation into immune deficient mice has revolutionized the fields of regenerative medicine and cancer biology. Yet, tools to facilitate direct visualization of the dynamic processes underlying carcinogenesis, tumor progression and metastasis in vivo remain limited. Here, we develop optically clear, immune deficient zebrafish that have mutations in recombination activating gene 2 (rag2), DNA-dependent protein kinase (prkdc) and janus kinase 3 (jak3). RNA sequencing and single-cell transcriptional profiling of the blood showed that rag2 hypomorphic mutant zebrafish lack T cells, while prkdc deficiency resulted in lack of mature T and B cells and jak3 in T and putative Natural Killer (NK) cells. While all three mutant lines engraft fluorescent-labeled normal and malignant cells, only the prkdc mutant fish reproduced as homozygotes and survived injury following tail fin clip and cell transplantation. Engraftment into optically clear, prkdc-mutant adult zebrafish facilitated dynamic live cell imaging of muscle regeneration, repopulation of muscle stem cells within their endogenous niche, and muscle fiber fusion at single-cell resolution. Serial imaging approaches also uncovered stochasticity in fluorescent-labeled leukemia regrowth following competitive cell transplantation into prkdc-mutant fish, providing refined models to assess clonal dominance and progression in the zebrafish. Our experiments provide an optimized and facile transplantation model, the casper-strain prkdc mutant fish, for efficient engraftment and direct visualization of fluorescent-labeled normal and malignant cells at single-cell resolution.