The generation of different proteins from a single gene by alternative splicing of pre-mRNA is a process that is regulated in a time- and tissue-specific manner. Although initiated by extracellular signals, transmission of such information from the cell surface to nuclear splicing machinery is not fully understood. Weg-Remers et al. have made some progress with respect to the expression of variant isoforms of CD44 on the surface of T cells. Activation of primary T cells initiated the ERK, JNK, and p38 MAP kinase signaling cascades. Yet, activation of only the Ras-ERK pathway was needed to generate a mature form of CD44 that included a particular exon. Mutation of the splice-responsive elements within this exon reduced expression of the CD44 isoform in response to ERK activation. Splicing did not depend on protein synthesis and the authors propose that posttranslational modification of regulatory splice factors, possibly by phosphorylation, regulates pre-mRNA splicing. The specificity of exon selection could thus be determined in part by the activation of distinct signaling pathways.