Antimitotics, particularly microtubule-targeting agents (MTAs) like paclitaxel, have proven effective in cancer therapy. However, microtubules play crucial roles in various non-mitotic cellular processes such as directional trafficking, signaling, and motility. In addition to resistance issues, MTAs can, thus, be toxic to cells during interphase. Recent efforts have focused on developing new therapies targeting proteins involved in cell cycle regulation and mitosis. While some inhibitors progressed to clinical trials as monotherapy, many were discontinued due to unfavorable results. Nevertheless, these therapies shouldn't be dismissed. Building on recent insights into their mechanisms, new strategies could enhance their efficacy, warranting further clinical trials. We propose i) understanding the reasons behind the failures of these inhibitors in monotherapy trials; and ii) testing a strategy to boost their effectiveness against cancer, offering a second chance and facilitating the design of successful human therapy trials.