Lineage tracing has the promise to map out the lineage relationship among cells during development and differentiation. When integrated with single-cell profiling, it could systematically reveal the differentiation coupling across different cell states, and gain insights into the dynamic process of tissue development and cell differentiation. I will first briefly review the history of lineage tracing, and then focus on more recent efforts in developing mouse models that allow high-capacity lineage barcoding in vivo. Finally, I will talk about how to integrate transcriptome, epigenome, and lineage profiling to systematically investigate the molecular determinants of cell differentiation. Computational challenges for extracting information from such lineage tracing datasets will also be highlighted.