Laulimalide is a structurally unique 20-membered marine macrolide displaying microtubule stabilizing activity similar to that of paclitaxel and the epothilones. The use of atom-economical transformations such as a Rh-catalyzed cycloisomerization to form the endocyclic dihydropyran, a dinuclear Zn-catalyzed asymmetric glycolate aldol reaction to prepare the syn 1,2-diol, and an intramotecular Ru-catalyzed alkene-alkyne coupling to build the macrocycle enabled us to synthesize laulimalide via an efficient and convergent pathway. The designed synthetic route also allowed us to prepare an analogue of the natural product that possesses significant cytotoxic activity.