The Hippo signaling pathway was identified through genetic screens in Drosophila that were designed to identify novel genes involved in organ size control. In flies, mutations in core components of the Hippo signaling pathway, including the serine-threonine kinases Hippo and Warts lead to tissue overgrowth, in part by enhancing proliferation and inhibiting apoptosis. Direct orthologs of these and other core Hippo signaling components are found in mammals and they have been shown to function in an analogous kinase cascade to inhibit the activity of Yap and Taz, transcriptional co-activators orthologous to Drosophila yorkie. Despite conservation at the biochemical level, little is known about the requirements for core Hippo signaling pathway components in mammalian growth control. Here we describe our recent studies that employ conditional mutagenesis to delineate essential requirements for core Hippo signaling components in mammalian organ size regulation and in tumor suppression.