Pre-mRNA splicing is the removal of introns and ligation of exons to form mature mRNAs, and it provides a critical mechanism by which eukaryotic cells can regulate their gene expression. Strikingly, more than 90% of protein-encoding transcripts are alternatively spliced, through exon inclusion/skipping, differential use of 5' or 3' alternative splice sites, intron retention or selection of an alternative promoter, thereby drastically increasing protein diversity. Splicing is altered in various pathological conditions, including cancers. In the last decade, high-throughput transcriptomic analyses have identified thousands of splice variants in cancers, which can distinguish between tumoral and normal tissues as well as identify tumor types, subtypes and clinical stages. These abnormal or aberrantly expressed splice variants, found in all cancer hallmarks, can result from mutations in splice sites, deregulated expression or even somatic mutations of components of the spliceosome machinery. Therefore, and based on these recent observations, a new anti-cancer strategy of targeting the spliceosome machinery with small molecules has emerged; however, the potential for these therapies is still a matter of great debate. Notably, more preclinical studies are needed to clarify which splicing patterns are mainly affected by these compounds, which cancer patients could be the most eligible for these treatments and whether using these spliceosome inhibitors alone or in combination with chemotherapies or targeted therapies would provide better therapeutic benefits. In this commentary, I will discuss all of these aspects.