Alternative splicing is a powerful means of controlling gene expression and increasing protein diversity. Most genes express a limited number of mRNA isoforms, but there are several examples of genes that use alternative splicing to generate hundreds, thousands, and even tens of thousands of isoforms. Collectively such genes are considered to undergo complex alternative splicing. The best example is the Drosophila Down syndrome cell adhesion molecule (Dscam) gene, which can generate 38,016 isoforms by the alternative splicing of 95 variable exons. In this review, we will describe several genes that use complex alternative splicing to generate large repertoires of mRNAs and what is known about the mechanisms by which they do so.