Burkholderia cepacia complex (Bcc) is an important and virulent pathogen in cystic fibrosis patients. The interactions between this pathogen and the host lung epithelium are being widely investigated but remain to be elucidated. The complex is very versatile and its interactions with the lung epithelial cells are many and varied. The first steps in the interaction are penetration of the mucosal blanket and subsequent adherence to the epithelial cell surface. A range of epithelial receptors have been reported to bind to Bcc. The next step in pathogenesis is the invasion of the lung epithelial cell and also translocation across the epithelium to the serosal side. Furthermore, pathogenesis is mediated by a range of virulence factors that elicit their effects on the epithelial cells. This review outlines these interactions and examines the therapeutic implications of understanding the mechanisms of pathogenesis of this difficult, antibiotic-resistant, opportunistic pathogen.