The identification of potent spliceosome modulators that demonstrate antitumor activity indicates that this complex may be a target for drug development. Several natural products have been demonstrated to bind to the SF3b1 subunit of this macromolecule and these agents modulate alternative RNA splicing. This article describes their biological properties, discuss the validity of the spliceosome as a therapeutic target, and propose that alteration of alternative splicing represents a viable approach for inducing tumor-selective cytotoxicity.