Cell fate decision is a critical step during physiological development when embryonic stem cells commit to either becoming adult stem cells or somatic cells. Recent advances in reprogramming demonstrate that a similar set of transcription factors (TFs), which are important for maintaining the pluripotent state of stem cells, can also reprogram somatic cells to induced pluripotent stem cells (iPSCs). In addition, trans-differentiation, which entails the use of different sets of defined factors, whereby one type of somatic cell can be directly converted into another and even to cell types from different germ layers has become a parallel widely used approach for switching cell fate. All these progresses have provided powerful tools to manipulate cells for basic science and therapeutic purposes. Besides protein-based factors, non-coding RNAs (ncRNAs), particularly microRNAs and long ncRNAs, are also involved in cell fate determination, including maintaining self-renewal of pluripotent stem cells and directing cell lineage. Targeting specific ncRNAs represents an alternative promising approach to optimize cell-based disease modeling and regenerative therapy. Here we focus on recent advances of ncRNAs in cell fate decision, including ncRNA-induced iPSCs and lineage conversion. We also discuss some underlying mechanisms and implications in molecular pathogenesis of human diseases.