Cystic Fibrosis results from mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The gene was identified in 1989, but more than 20 years later, the regulatory mechanisms controlling its complex expression are still not fully understood. Though the promoter binds transcription factors and drives some aspects of CFTR gene expression, it cannot alone account for tissue specific control. This implicates other distal cis-acting elements in cell-type-specific regulation of CFTR expression. Several of these elements, including intronic enhancers and flanking insulators, were identified within or near the CFTR locus. Here we summarize the known regulatory mechanisms controlling CFTR transcription, including those acting through elements in the promoter and others elsewhere in the locus. A special focus will be elements that contribute to tissue specific regulation of expression.