The major research efforts of the Kishi group are focused on the total syntheses of various complex natural products, typified by the completed works of neurotoxins (palytoxin, tetrodotoxin, etc.), antitumor antibiotics (halichondrins, mitomycins, etc.), polyether antibiotics (lasalocid A, monensin, etc.), metabolites of microorganisms (gliotoxins, etc.), and others. In order to carry out these syntheses, not only new synthetic strategies but also new synthetic methods are investigated. Current programs in this area include: the total synthesis of halichondrin A, an antitumor polyether macrolide isolated from marine sponges, and the development of catalytic asymmetric Cr-mediated coupling reactions.

In addition, the Kishi group has extensively been engaged with the structure elucidation of complex natural products via organic synthesis, as exemplified by the stereochemistry assignment of palytoxin and maitotoxin. This line of work has evolved to the universal NMR database approach, which allows assignment of the relative and absolute configuration of unknown compounds without degradation and/or derivatization. Noteworthily, the stereochemistry of mycolactones, the causative toxins of Buruli ulcer, has been established by this approach.