The human cytochrome P450 (CYP) superfamily of enzymes regulate hepatic phase 1 drug metabolism and subsequently play a significant role in pharmacokinetics, drug discovery and drug development. Alternative splicing of the cytochrome CYP gene transcripts enhances gene diversity and may play a role in transcriptional regulation of certain CYP proteins. Tissue-specific alternative splicing of CYPs is significant for its potential to add greater dimension to differential drug metabolism in hepatic and extrahepatic tissues, such as the brain, and to our understanding of the CYP family. This review provides an overview of tissue-specific splicing patterns, splicing types, regulation and the functional diversities between liver and splice variant CYP proteins and further explores the relevance of tissue-specific alternative splicing of CYPs in the nervous system.