Pre-mRNA splicing is a critical process in human gene expression, and disruptions in this process can lead to various diseases. The review highlights the mechanisms by which splicing errors contribute to human disease. The splicing machinery, composed of snRNPs and over 100 proteins, recognizes classical splice sites and catalyzes the removal of introns. Splicing errors can result in the production of abnormal mRNAs, leading to loss of function or the expression of inappropriate protein isoforms. Alternative splicing allows for the generation of multiple mRNA variants from a single gene, contributing to proteomic diversity. However, disruptions in alternative splicing can lead to disease by altering the expression of protein isoforms. Splicing errors can be classified into cis-acting and trans-acting mutations. Cis-acting mutations affect the use of specific splice sites, while trans-acting mutations affect the splicing machinery or regulatory factors. Several diseases are caused by mutations that disrupt splicing. For example, familial isolated growth hormone deficiency type II (IGHD II) is caused by mutations in the GH-1 gene, leading to altered splicing of exon 3. Frasier syndrome is caused by mutations in the WT-1 gene, affecting the splicing of exon 9. Frontotemporal dementia and Parkinsonism linked to Chromosome 17 (FTDP-17) is caused by mutations in the MAPT gene, which affect the splicing of exon 10. Atypical cystic fibrosis is caused by mutations in the CFTR gene, leading to altered splicing of exon 9. Disruptions in the basal splicing machinery can also cause disease. Retinitis pigmentosa (RP) is caused by mutations in genes involved in the function of the U4/U6·U5 tri-snRNP. Spinal muscular atrophy (SMA) is caused by mutations in the SMN gene, leading to the loss of SMN protein, which is essential for the assembly of snRNPs. The cell-specific effects of these mutations are likely due to the different requirements for splicing factors in different tissues. The review emphasizes the importance of understanding splicing defects in the context of human disease and the need for further research into the mechanisms underlying these defects.Pre-mRNA splicing is a critical process in human gene expression, and disruptions in this process can lead to various diseases. The review highlights the mechanisms by which splicing errors contribute to human disease. The splicing machinery, composed of snRNPs and over 100 proteins, recognizes classical splice sites and catalyzes the removal of introns. Splicing errors can result in the production of abnormal mRNAs, leading to loss of function or the expression of inappropriate protein isoforms. Alternative splicing allows for the generation of multiple mRNA variants from a single gene, contributing to proteomic diversity. However, disruptions in alternative splicing can lead to disease by altering the expression of protein isoforms. Splicing errors can be classified into cis-acting and trans-acting mutations. Cis-acting mutations affect the use of specific splice sites, while trans-acting mutations affect the splicing machinery or regulatory factors. Several diseases are caused by mutations that disrupt splicing. For example, familial isolated growth hormone deficiency type II (IGHD II) is caused by mutations in the GH-1 gene, leading to altered splicing of exon 3. Frasier syndrome is caused by mutations in the WT-1 gene, affecting the splicing of exon 9. Frontotemporal dementia and Parkinsonism linked to Chromosome 17 (FTDP-17) is caused by mutations in the MAPT gene, which affect the splicing of exon 10. Atypical cystic fibrosis is caused by mutations in the CFTR gene, leading to altered splicing of exon 9. Disruptions in the basal splicing machinery can also cause disease. Retinitis pigmentosa (RP) is caused by mutations in genes involved in the function of the U4/U6·U5 tri-snRNP. Spinal muscular atrophy (SMA) is caused by mutations in the SMN gene, leading to the loss of SMN protein, which is essential for the assembly of snRNPs. The cell-specific effects of these mutations are likely due to the different requirements for splicing factors in different tissues. The review emphasizes the importance of understanding splicing defects in the context of human disease and the need for further research into the mechanisms underlying these defects.