Alternative splicing is a post-transcriptional mechanism that can substantially change the pattern of gene expression. Proper regulation of alternative splicing is important for cell physiology, and aberrant splicing may lead to clinical manifestations. Cellular signals or environmental stimuli can determine the outcome of alternative splicing through trans-acting splicing regulatory factors. Networks of signaling cascades may post-translationally modify these splicing factors, thereby altering their subcellular localization or activity and hence impacting pre-mRNA splicing. Moreover, some extracellular signals, mostly steroid hormones, may regulate alternative splicing through a transcription-coupled splicing mechanism. Nevertheless, further intensive investigation will be needed to fully understand the intricacies of signal-mediated alternative splicing control.