The targeting of microtubules is an important mechanism for cancer chemotherapy. However, there is still a need for improved antimicrotubule agents. A number of seemingly structurally disparate peptidic natural products inhibit tubulin polymerization by binding to a region of the tubulin heterodimer close to the vinca binding site. An analogue of the naturally occurring tripeptide hemiasterlin, taltobulin (HTI-286, 3), has advanced to clinical trials. Structure-activity relationship studies of 3 have revealed critical structural elements necessary for antimicrotubule activity that correspond to comparable groups in the amino terminus tripeptide region of the dolastatins. To investigate the structural relationship between the hemiasterlins and the more complex dolastatins, hybrid compounds composed of 3 and the carboxy terminus dipeptides of dolastatin 10, or the dolastatin 15 analogue cemadotin, were synthesized. The resulting hybrid compounds were potent antimicrotubule agents, thus establishing a structural relationship between the hemiasterlins and the dolastatins. This relationship may be useful in the design of analogues having improved activity in resistant cell lines expressing the P-glycoprotein transporter, for establishing structural relationships with other classes of peptidic antimicrotubule agents, or for modeling studies of the tubulin binding site of these agents.