It is clear that RNA is more than just a messenger between gene and protein. The mammalian genome is pervasively transcribed, giving rise to tens of thousands of non-coding transcripts. Whether all of these transcripts are functional remains to be elucidated, but it is evident that there are many functional long non-coding RNAs (lncRNAs). Recent studies have set out to decode the regulatory role and functional diversity of lncRNAs. Here we organize these studies to highlight the significant involvements of lncRNAs in regulation of gene expression and human physiological and pathological processes, which are achieved by their interaction with DNA, RNA or protein.