The zebrafish has emerged as a powerful new vertebrate model of human disease. Initially prominent in developmental biology, the zebrafish has now been adopted into varied fields of study including immunology. In this review, we describe the characteristics of the zebrafish, which make it a versatile model, including a description of its immune system with its remarkable similarities to its mammalian counterparts. We review the zebrafish disease models of innate and adaptive immunity. Models of immune system malignancies are discussed that are either based on oncogene over-expression or on our own forward-genetic screen that was designed to identify new models of immune dysregulation.