Monopolar spindle kinase 1 (MPS1) plays a pivotal role as a dual-specificity kinase governing spindle assembly checkpoint activation and sister chromatid separation in mitosis. Its overexpression has been observed in various human malignancies. MPS1 reduces spindle assembly checkpoint sensitivity, allowing tumor cells with a high degree of aneuploidy to complete mitosis and survive. Thus, MPS1 has emerged as a promising candidate for cancer therapy. Despite the identification of numerous MPS1 inhibitors, only five have advanced to clinical trials with none securing FDA approval for cancer treatment. In this perspective, we provide a concise overview of the structural and functional characteristics of MPS1 by highlighting its relevance to cancer. Additionally, we explore the structure-activity relationships, selectivity, and pharmacokinetics of MPS1 inhibitors featuring diverse scaffolds. Moreover, we review the reported work on enhancing MPS1 inhibitor selectivity, offering valuable insights into the discovery of novel, highly potent small-molecule MPS1 inhibitors.