Invertebrate animal models (mainly the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster) are gaining momentum as screening tools in drug discovery. These organisms combine genetic amenability, low cost, and culture conditions compatible with large-scale screens. Their main advantage is to allow high-throughput screening in a physiological context. On the down side, protein divergence between invertebrates and humans causes a high rate of false negatives. Despite important limitations, invertebrate models are an imperfect yet much needed tool to bridge the gap between traditional in vitro and preclinical animal assays.