<p>Despite advances in the current treatment strategies for breast cancer management, chemotherapeutic resistance and recurrence are now recognised as a substantial global health problem. Microtubule-targeting agents are key clinical candidates in breast cancer therapy that abrogate tubulin dynamics, lead to arrest in mitosis, and enhance apoptosis of cancer cells. However, traditional agents like taxanes and vinca alkaloids suffer from the serious issue of toxicity, suboptimal pharmacokinetics, and multidrug resistance. Novel scaffolds and molecular hybrids have been reported to exhibit potent activity against resistant breast cancer cells by targeting the colchicine or taxane sites of tubulin. In addition, multi-targeting and dual-targeting ligands showed interesting combinatory effects. This review discusses the design strategies, structure-activity relationship studies, and pharmacological knowledge of a new class of microtubule-targeting agents to encourage further scope in the development of next-generation, selective, and safer antimitotic agents for better management of breast cancers.</p>