Because of their small size, high fecundity, and commonality to human genetics and genomics, phenotype-based animal testing using zebrafish (Danio rerio) has emerged as a powerful tool for identifying disease mechanisms, drug target molecules and small bioactive compounds over the last decade. Importantly, the immaturity of the zebrafish larvae immune system compared with that of mammals facilitates the implantation of human tumors representing aggressive cancer progression with metastasis. In the current chapter, we describe the methods for human cancer cell xenotransplantation into zebrafish, phenotypic image analysis, and transcriptome analysis using deep sequencing.