The CLCA proteins were first shown to exist in bovine trachea and named as chloride channels calcium activated (CLCA) due to the calcium-dependent chloride conductance that appeared to be activated on expression of these proteins in trachea and other secretory epithelial cells. Since their initial discovery the CLCA gene family has grown extensively and family members have been identified in bovine, human, murine, equine and porcine tissues. The CLCA proteins appear to have a role to play in chloride conductance across epithelial cells and hence epithelial fluid secretion; cell-cell adhesion, apoptosis, cell cycle control and tumorgenesis and metastasis; mucous production and cell signalling in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). There are four human homologues; hCLCA1, hCLCA2, hCLCA3 and hCLCA4. Interest in these proteins has gathered pace with the description of hCLCA1's involvement in several human respiratory diseases. This review will describe the CLCA gene family and then move on to look at the growing body of evidence that suggests that at least hCLCA1 has an important role in the pathogenesis of respiratory disease such as asthma, COPD and cystic fibrosis (CF).