Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remains mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis reveals that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors, potentially disrupt protein-protein interactions in cancer-related pathways, and are mutually exclusive with mutations in multiple cancer drivers. Moreover, there is a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors represents independent oncogenic processes and could potentially be considered alternative splicing drivers (AS-drivers).