Concerns about chemical contamination of the food supply and the potential risks to human populations, particularly children, emphasize the need for rapid screening methods. However, designing test systems that are both robust and reliable, but not prohibitively expensive, is challenging. Moreover, the methods selected must also be compatible with the need to reduce, refine and replace animal testing. Most alternative methods are in vitro cellular- or molecular-based screening tests that focus on key aspects of a signalling process. One advantage of most in vitro tests is their high-throughput capacity. Two common disadvantages are the use of single-cell types or modelling of single receptor–ligand interactions and the lack of metabolic competence that in vivo models possess. A number of small model organisms (SMOs) are being developed for screening purposes, including the nematode, Caenorhabitis elegans, the fruitfly, Drosophila melanogaster, and two vertebrates, the zebrafish, Danio rerio, and the anuran amphibian, Xenopus laevis. Each of these vertebrate models share a number of key advantages: low stabulation costs, sizes that are suitable for large-scale screening programs in multiple-well plates and transparency of the embryo, allowing for easy detection of fluorescent protein expression in the living animal. Another major advantage is that these models are ideal for genetic modification, allowing the production of transgenics, e.g. for engineering specific reporter systems. The combination of each of these key features provides their overall advantage, that of permitting fluorescence-based high-throughput screening with a whole organism, at the in vitro/in vivo interface.