The Hannon laboratory comprises a broad spectrum of programs in small RNA biology, mammalian genetics and genomics. We study RNAi and related pathways in a wide variety of organisms to extract common themes that define both the mechanisms by which small RNAs act and the biological processes which they impact. Currently, we focus on microRNAs, endogenous siRNAs and piRNAs and their roles in gene regulation, cancer biology, stem cell biology and in defense of the genome against transposons. We develop genome-wide shRNA tools for RNAi-based genetics in mammalian cells, and we are now producing similar collections of artificial microRNAs for Arabidopsis. Our genomic efforts include the application of RNAi-based genetic screens to cancer biology and stem cells. We also make heavy use of next generation sequencing methodologies for probing small RNA populations, in part as a member of the ENCODE consortium. Finally, we develop and apply focal re-sequencing methods for identifying disease relevant mutations, for probing the epigenetic landscape and for the study of human evolution.