Congenital heart defects (CHDs) are among the most common human birth defects. However, the etiology of a large proportion of CHDs remains undefined. Studies identifying the molecular and cellular mechanisms that underlie cardiac development have been critical to elucidating the origin of CHDs. Building upon this knowledge to understand the pathogenesis of CHDs requires examining how genetic or environmental stress changes normal cardiac development. Due to strong molecular conservation to humans and unique technical advantages, studies using zebrafish have elucidated both fundamental principles of cardiac development and have been used to create cardiac disease models. In this chapter we examine the unique toolset available to zebrafish researchers and how those tools are used to interrogate the genetic and environmental contributions to CHDs.