The spliceosome has been shown to be a promising target for the development of new anticancer therapeutics. Synthetic and chemical biological efforts directed toward the development of natural product-based splice modulators (SPLMs) have shown that the potency of these compounds derives from their ability to selectively affect the alternate splicing of apoptotic genes in tumor cells. However, questions remain regarding the mechanistic understanding of splice modulation as well as the selectivity with which SPLMs impact certain genes.