The entire world is looking for effective cancer therapies whose benefits would outweigh their toxicity. One way to reduce resistance to chemotherapy and its adverse effects is the so called targeted therapy, which targets specific molecules ("molecular targets") that play a critical role in cancer growth, progression, and metastasis. One such specific target are microtubules. In this review we address the current knowledge about microtubule-targeting agents or drugs (MTAs/MTDs) used in cancer therapy from their synthesis to toxicities. Synthetic and natural MTAs exhibit antitumor activity, and preclinical and clinical studies have shown that their anticancer effectiveness is higher than that of traditional drug therapies. Furthermore, MTAs involve a lower risk of adverse effects such as neurotoxicity and haemotoxicity. Several new generation MTAs are currently being evaluated for clinical use. This review brings updated information on the benefits of MTAs, therapeutic approaches, advantages, and challenges in their research.