AbstractAs a powerful genetic tool, site‐specific recombinases (SSRs) have been widely used in genomic manipulation to elucidate cell fate plasticity in vivo, advancing research in stem cell and regeneration medicine. However, the low resolution of conventional single‐recombinase‐mediated lineage tracing strategies, which rely heavily on the specificity of one marker gene, has led to controversial conclusions in many scientific questions. Therefore, different SSRs systems are combined to improve the accuracy of lineage tracing. Here we review the recent advances in dual‐recombinase‐mediated genetic approaches, including the development of novel genetic recombination technologies and their applications in cell differentiation, proliferation, and genetic manipulation. In comparison with the single‐recombinase system, we also discuss the advantages of dual‐genetic strategies in solving scientific issues as well as their technical limitations.