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Simple Summary: The spliceosome ribonucleoprotein complex catalyzes the removal of introns and exons ligation, a fundamental post-transcriptional process that generates mature RNAs. Cancer-associated mutations in spliceosome components give rise to aberrant splice site selection and, therefore, the production of novel isoform variants that support tumorigenesis. In this review, we summarize the current research regarding cancer hotspot mutations identified in spliceosome components acting at the very first step of splicing, namely the U1 snRNA, SF3B1, and U2AF1. Splicing alterations have been widely documented in tumors where the proliferation and dissemination of cancer cells is supported by the expression of aberrant isoform variants. Splicing is catalyzed by the spliceosome, a ribonucleoprotein complex that orchestrates the complex process of intron removal and exon ligation. In recent years, recurrent hotspot mutations in the spliceosome components U1 snRNA, SF3B1, and U2AF1 have been identified across different tumor types. Such mutations in principle are highly detrimental for cells as all three spliceosome components are crucial for accurate splice site selection: the U1 snRNA is essential for 3′ splice site recognition, and SF3B1 and U2AF1 are important for 5′ splice site selection. Nonetheless, they appear to be selected to promote specific types of cancers. Here, we review the current molecular understanding of these mutations in cancer, focusing on how they influence splice site selection and impact on cancer development. [ABSTRACT FROM AUTHOR]