Ribonucleic acid (RNA) splicing dysregulation is considered a molecular hallmark and important therapeutic target of cancer. Although targeting splicing has been intensively pursued for cancer therapy, specific modulators of dysregulated splicing factors are generally lacking. RNA binding motif protein 10 (RBM10) is frequently mutated in multiple cancers, in particular lung adenocarcinoma (LUAD). Increasing evidence has demonstrated that RBM10 deficiency due to loss-of-function (LOF) mutation or aberrant expression contributes to cancer development, progression, and therapeutic response. Here, we summarize the functional consequences and new therapeutic implications of RBM10 deficiency in cancer. Using RBM10 as a representative example, we highlight main strategies for targeting dysregulated splicing factors. These strategies, either alone or in combination with currently approved therapies, may hold great promise in cancer treatment.