A plethora of clinically distinct human disorders exist whose underlying cause is a defect in the response to or repair of DNA damage. The clinical spectrum of these conditions provides evidence for the role of the DNA damage response (DDR) in mediating diverse processes such as genomic stability, immune system function and normal human development. Cell lines from these disorders provide a valuable resource to help dissect the consequences of compromised DDR at the molecular level. Here we will discuss some well known, less well known and 'novel' DDR defective disorders with particular reference to the functional interplay between the DNA damage response and cell cycle checkpoints. We will describe recent advances in further delineating the genetic basis of Seckel syndrome and microcephalic osteodysplastic primordial dwarfism type II, which have shed more light on the interplay between the DDR, cycle progression and centrosomes. We will also overview recent developments concerning haploinsufficiency of DDR components and their association with certain genomic disorders such as Miller-Dieker lissencephaly syndrome and Williams-Beuren syndrome. Finally, we will discuss how defects in the DDR result in some unexpected clinical features before describing how the nature of a DDR defect impacts on the management and treatment of individuals with these conditions.