The advent of new CRISPR-based molecular tools allows the reconstruction of cell lineages based on the phylogenetical analysis of DNA mutations induced by CRISPR during development and promises to solve the lineage of complex model organisms at single-cell resolution. To date, however, no lineage reconstruction algorithms have been rigorously examined for their performance/robustness across diverse molecular tools, datasets, and number of cells/size of lineage trees. It also remains unclear whether new Machine-Learning algorithms that go beyond the classical ones developed for reconstructing phylogenetic trees, could consistently reconstruct cell lineages to a high degree of accuracy. The challenge – a partnership between The Allen Institute and DREAM – will comprise 3 subchallenges that consist of reconstructing cell lineage trees of different sizes and nature.