Marine organisms have attracted scientific community as a rich source of natural products with unusual structural features and remarkable biological activities. Marine macrolides are a prominent class of natural products characterized by a highly oxygenated polyene backbone containing a macrocyclic lactone as a conformational constraint. Many marine macrolides possess outstanding cell growth antiproliferative properties, making them valuable molecular probes for the investigation of biochemical pathways and promising lead compounds for the development of new antitumor chemotherapeutic agents. In the present review we intend to focus on marine macrolides with potent cytotoxic activity that could be exploited in cancer research and therapy, along with those macrolides currently in clinical trials and/or preclinical development.