Cystic fibrosis (CF) is the commonest autosomal recessive condition among Caucasian populations, affecting 1 in 2500 live births. The median age of survival has dramatically improved and will reach 40 years for children born in the 1990s. Complications such as cystic fibrosis related diabetes mellitus (CFRD) develop with age, and the median age at diagnosis is 21 years. The prevalence of CFRD progressively increases from 9% below the age of 10 years to 43% above the age of 30 years, with reported annual age-dependent incidence rates ranging from 4% to 9%. The onset of CFRD is insidious and annual screening using the standard oral glucose tolerance test (OGTT) from the age of 10 years has been recommended. However, OGTT thresholds for the diagnosis of impaired glucose tolerance and CFRD were derived from epidemiological studies of non-CF patients and it is uncertain whether they are appropriate for patients with CF. The ability of OGTT alone to detect early abnormalities in blood glucose regulation has been questioned. Continuous glucose monitoring systems (CGMS) may augment the screening and diagnosis of CFRD, as well as guide and monitor its management. Subcutaneous insulin therapy is currently recommended for the treatment of CFRD. Early use of insulin therapy might improve weight gain and lung function of CF patients, including those with normal OGTT results. It is still not clear when insulin therapy should be started, possibly reflecting the difficulties in detecting early but clinically relevant abnormalities in blood glucose metabolism among CF patients. We review the current evidence which highlight these diagnostic and management challenges in CFRD.