Cryptophycins are a class of 16‐membered highly cytotoxic macrocyclic depsipeptides isolated from cyanobacteria. The biological activity is based on their ability to interact with tubulin. They interfere with microtubule dynamics and prevent microtubules from forming correct mitotic spindles, which causes cell‐cycle arrest and apoptosis. Their strong antiproliferative activities with 100‐fold to 1000‐fold potency compared with those of paclitaxel and vinblastine have been observed. Cryptophycins are highly promising drug candidates, as their biological activity is not negatively affected by P‐glycoprotein, a drug efflux system commonly found in multidrug‐resistant cancer cell lines and solid tumors. Cryptophycin‐52 had been investigated in phase II clinical trials but failed because of its high neurotoxicity. Recently, cryptophycin conjugates with peptides and antibodies have been developed for targeted delivery in tumor therapy. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.