Reconstructing lineage relationships between cells within a tissue or organism is a long-standing aim in biology. Traditionally, lineage tracing has been achieved through the (genetic) labeling of a cell followed by the tracking of its offspring. Currently, lineage trajectories can also be predicted using single-cell transcriptomics. Although single-cell transcriptomics provides detailed phenotypic information, the predicted lineage trajectories do not necessarily reflect genetic relationships. Recently, techniques have been developed that unite these strategies. In this Review, we discuss transcriptome-based lineage trajectory prediction algorithms, single-cell genetic lineage tracing, and the promising combination of these techniques for stem cell and cancer research.