Alternative splicing of pre-mRNA leads to variation in the exons that form the mRNA, and provides eukaryotic organisms with an additional qualitative control of gene expression. Disruptions in the regulation of pre-mRNA splicing caused by heritable genomic mutations or quantitative shifts in the regulation of exon inclusion can lead to disease. Alternative exon inclusion (pre-mRNA splicing) produces different proteins with alternative activities, derived from the same pre-mRNA, and is utilized by the immune system to expand gene function. Recent advances in the delivery of splice switching oligomers to lymphoid cells, combined with the ability to manipulate mRNA splicing to either correct mis-splicing or to alter the balance of different splice forms, holds great promise for the development of new therapeutic strategies for the treatment of immune-related disease. Antisense-based targeted manipulation of various immune modulating molecules as therapeutic approaches are discussed in this review.