Vinca alkaloids represent a chemical class of major interest in cancer chemotherapy. The lead compounds vinblastine and vincristine have been employed in clinical practice for more than thirty years and remain widely used to this day. Several hundred derivatives have been synthesised and evaluated for their pharmacological activities, the majority being modified in the vindoline moiety, bearing several reactive centers. These efforts led to the identification of the amido derivative vindesine, registered in Europe in 1980 and now available in several countries. Then novel chemistry permitted the semisynthesis of derivatives modified in the velbenamine or upper part of the molecule, creating a new potential in the Vinca alkaloids medicinal chemistry: as a result, vinorelbine, obtained by C ring contraction of anhydrovinblastine, and is now marketed worlwide. Several strategies aimed at the total synthesis of vinblastine derivatives have been investigated, giving the opportunity to design rationaly c ertain compounds. Modifications in the D ring appeared to induce dramatic changes in the tubulin interactions. These observations have been confirmed recently by the identification of unprecedented pharmacological properties exerted by the novel fluorinated Vinca alkaloid, vinflunine. This review will focus more specifically on derivatives which have been modified in the velbenamine part, with the aim of inducing different chemical and pharmacological properties.