Microtubules-targeting agents (MTAs) are an attractive class of compounds that has been broadly used in cancer treatment since the 1960s. Their main mechanism of action is based on their interaction with microtubules, one of the principal components of the cell cytoskeleton, blocking cell division at the mitotic phase. The main issues with the use of MTAs are their scarce selectivity, as microtubules are present in all cells, and the multi-drug resistance (MDR) of cancer cells. The ideal MTA should selectively attack cancer cells and elude multi-drug resistance mechanisms. Selectivity can be achieved by targeting tubulin isotypes that are overexpressed in tumor tissues, while MDR can be eluded by avoiding interaction between the drug and transmembrane efflux pumps such as P-gp.