GWAS and more recently whole-exome/genome sequencing have generated a massive expansion in the number of candidate disease genes. Animal models will have an essential role in validating candidate genes and understanding their role in pathobiology. Advances in targeted genome engineering with TALENs and CRISPRs now makes it feasible for individual laboratories to generate heritable and precise sequence modifications of their gene of interest in any organism. Zebrafish are an attractive model system because they share the vast majority of human disease genes. Genome editing tools such as CRISPR-Cas9 and TALENs permit heritable and precise sequence modification of the genome. In this session I will discuss the strengths and weaknesses of the new genome editing tools and compare these methods to existing gene knock-down approaches. I will provide a brief overview of how we are applying these exciting genome editing tools to generate more informative models of human disease.