Alternative processing of primary RNA transcripts has been found across all eukaryotes, in unicellular parasites and flagellates as well as in green algae, plants and, of course, fungi, and animals. Alternative splicing, therefore, is a characteristic of the last eukaryotic common ancestor. It is used to increase proteome diversity and has been shown to be highly regulated in many species. Many different types of alternative splicing exist, like differential inclusion of exons, intron retention, or alternative 5’- and 3’-splicing of exons. A particularly interesting case is mutually exclusive splicing, in which neighboring exons are spliced in a mutually exclusive manner into the mature transcript. The most extreme case reported so far is the Drosophila Down Syndrome Cell Adhesion Molecule (Dscam) gene that contains four clusters of mutually exclusive spliced exons (MXEs) with 93 alternative exons in the genomic sequence (Figure 1). Although MXEs within a cluster are relatively similar, they cannot substitute each other if one is damaged. In humans, mutations in MXEs have been shown to cause diseases like the Timothy syndrome, cardiomyopathy, or cancer. The regulation of MXE splicing and their evolutionary conservation have been studied in great detail for a few example genes like Dscam and the insect muscle myosin heavy chain (Mhc) genes. However, a concise analysis of MXEs within an entire genome has been missing to date.