Alternative splicing of pre-mRNA is a major contributor to protein diversity. An estimated 75% of human genes are alternatively spliced, and tissue specific splicing is highest in the brain. Some 15% of genetic disorders are caused by point mutations found in splice site sequences and predicted to alter splicing. Moreover, alternative splicing is emerging as a major factor in the regulation of protein function and gene expression. For these reasons, the Wolfe Lab has begun studying alternative splicing as it relates to Alzheimer’s and other neurodegenerative diseases. We seek to advance the understanding of pre-mRNA splicing of genes known to be involved in pathogenesis and to identify strategies for modulation of splicing events for potential therapeutic purposes. Small molecule modulation through interaction with mRNA secondary structure is of special interest, as few pharmacological agents interact with RNA, and none target specific RNA sequences and alter splicing. The development of a general strategy toward the discovery of small molecules that modulate specific splicing events would have broad implications for biology and medicine.