Nature has yielded numerous compounds that bind to tubulin/microtubules and disrupt microtubule function. Even with the advent of targeted therapies for cancer, natural products and their derivatives that target microtubules are some of the most effective drugs used in the treatment of solid tumors and hematological malignancies. For decades, these drugs were thought to work solely through their ability to inhibit mitosis. Accumulating evidence demonstrates that their actions are much more complex, in that they also have significant effects on microtubules in nondividing cells that inhibit a diverse range of signaling events important for carcinogenesis. The abilities of these drugs to inhibit oncogenic signaling likely underlies their efficacy, especially in solid tumors. In this review, we describe the role of microtubules in cells, the proliferation paradox of cells in culture as compared to cancers in patients, and evidence that microtubule-targeting drugs inhibit cellular signaling pathways important for tumorigenesis. The potential mechanisms behind differences in the clinical indications and efficacy of these natural-product-derived drugs are also discussed. Microtubules are an important target for structurally diverse natural products, and a fuller understanding of the mechanisms of action of these drugs will promote their optimal use.