One of the major challenges in cancer treatment today is that many patients develop resistance to the therapeutic agents, resulting in treatment failure. Alternative splicing can significantly alter the coding region of drug targets. Here, we highlight several reports that provide key examples of alternative splicing events that occur in various cancers and play a role in resistance to cancer therapy. These examples present prime targets for future study and development of splicing modulation therapy. Modulation of alternative splicing has recently been approved as treatment for several diseases, although not yet for cancer. We propose that a similar approach may be successfully adapted to combat cancer therapy resistance, in cases where alternative splicing is known to be the mechanism that contributes to the resistance.