One of the main strategies for the treatment of cancer is chemotherapy used either alone or in combination with surgery,radiotherapy or other new approaches developed day by day during these years.Among the huge number of cytotoxic drugs on the pharmaceutical market taxanes are on the first line in therapy but after few cycles of treatment, as usual, they are inducing resistance.The mechanism of resistance is mainly linked to the multidrug resistance phenotype mediated by the P-glycoprotein efflux pump, encoded by the mdr1 gene.Mutations of tubulin isotype genes have also been reported in taxoid resistant cell lines.The taxoid for these reasons are often of limited efficacy in chemotherapeutic regimens;and so new molecules with different mechanism of action are of strategic importance.In taxane field two molecules have been developed by us, one very effective on multidrug resistant cell lines while the second acts synergistically with the well known compounds of the family when metronomically administered every days between the usual therapeutic cycles.To bypass the tumor resistance new derivative of thiocolchicine have also been synthesized and developed up to Phase 1 clinical trial.The first modified taxane, Ortotaxel,is a compound very active on resistant cell lines and it is also orally bioavailable;this new compound has concluded the iv Phase 2 clinical trial and is entering in Phase 1 by oral administration.The second taxane compound, seco taxane IDN 5390 completed preclinical pharmacology and toxicology and it is going to enter in Phase 1 in combination with Paclitaxel.IDN 5390 in several human tumor xenografts including Paclitaxel resistant tumor improved consistently the life span of animals without increasing toxicity.A closer examination of the tubuline interaction shows a selective activity for the class Ⅲ of a β-tubulin overexpressed in paclitaxel resistant tumors.The thiocolchicine derivative,IDN 5404 was selected for its dual mechanism of action, inhibition of tubulin and topoisomerase 1 and for its cytotoxic activity at nm concentration in several cancer cell lines.IDN 5404 shows excellent antitumor activity as single agent against human tumor models including colon, prostate and ovarian cancer.In several models IDN 5404 is a new vascular disrupting agent.Controlled clinical trials are planned to verify the tolerability and the efficacy of these new molecules.