ABSTRACT The developmental cell lineage tree, which records every cell division event and the terminal developmental state of each single cell, is one of the most important traits of multicellular organisms, as well as key to many significant unresolved questions in biology. Recent technological breakthroughs are paving the way for direct determination of cell lineage trees, yet a general framework for the computational analysis of lineage trees, in particular an algorithm to compare two lineage trees, is still lacking. Based on previous findings that the same developmental program can be invoked by different cells on the lineage tree to produce highly similar subtrees, we designed D evelopmental C e ll L ineage T ree A lignment (DELTA), an algorithm that exhaustively searches for lineage trees with phenotypic resemblance in lineal organization of terminal cells, meanwhile resolving detailed correspondence between individual cells. Using simulated and nematode lineage trees, we demonstrated DELTA’s capability of revealing similarities of developmental programs by lineal resemblances. Moreover, DELTA successfully identifies gene deletion-triggered homeotic cell fate transformations, reveals functional relationship between mutants by quantifying their lineal similarities, and finds the evolutionary correspondence between cell types defined non-uniformly for different species. DELTA establishes novel foundation for comparative study of lineage trees, much like sequence alignment algorithm for biological sequences, and along with the increase of lineage tree data, will likely bring unique insights for the myriads of important questions surrounding cell lineage trees.