Platyfish and swordtails of the genus Xiphophorus provide a well-established model for melanoma research and have become well known for this feature. Recently, modelling approaches for other human diseases in Xiphophorus have been developed or are emerging. This Review provides a comprehensive summary of these models and discusses how findings from basic biological and molecular studies and their translation to medical research demonstrate that Xiphophorus models have face, construct and predictive validity for studying a broad array of human diseases. These models can thus improve our understanding of disease mechanisms to benefit patients.