It has become increasingly clear that the mammalian genome encoded numerous long noncoding RNA (lncRNA) genes. Our research program continues to push the forefront in understanding long noncoding RNAs (lncRNAs) from identifying and mapping thousands of lncRNA loci -- to developing numerous mutant lncRNA mouse models demonstrating the important impact of lncRNA loci in development and disease -- to dissecting the molecular modalities and mechanisms of lncRNAs in transcriptional and epigenetic regulation. Central to our approach is to bridge the computational and experimental sciences to identify functional long noncoding RNAs. This combinatorial and multi-faceted approach is critical to advance our understanding of how lncRNAs influence cell fate, transcriptional regulation and nuclear architecture. Underscoring the importance of this approach many of the lncRNAs we study are found to be implicated in human disease.