Dolastatin 10 is an extremely potent broad-spectrum antitubulin anticancer pentapeptide isolated from Dolabella auricularia. The two-dimensional structure was elucidated by NMR and mass spectrometric analyses. The absolute configuration was determined by a convergent total synthesis. SAR studies established that modifications at C- and N-terminals were tolerated for cytotoxic activity. Human clinical trials of dolastatin 10 and auristatin PE (a C-terminal analog) showed occasional signs of efficacy but failed due to lack of separation of toxicity and efficacy. Nanomolar cytotoxicity helped transition this class of pentapeptides to the next phase of development as antibody drug conjugates (ADCs) by reducing systemic toxicity. Four ADC drugs (Adcetris, Padcev, Polivy, and Blenrep) carrying monomethyl auristatin E (MMAE, vedotin) and monomethyl auristatin F (MMAF, mafodotin) payloads have been approved for treatment of a number of cancers expressing antibody-specific antigens. More than 36 ADCs carrying a variety of pentapeptide analogues are undergoing preclinical and clinical developments. They are being evaluated in more than 200 human trials. A comprehensive review of the discovery, total synthesis of dolastatin 10 and new amino acids, SAR studies of dolastatin 10 and auristatins, conjugations to antibodies, and preclinical and clinical development of ADCs have been presented.