The Karatau Fault System of southern Kazakstan forms a crustal-scale zone of strike-slip dominated transpressional tectonics which has undergone multiple phases and styles of deformation during a protracted history of reactivation from the Neoproterozoic to the Cenozoic. Ductile fabrics associated with dextral kinematic indicators are present in amphibolites along the Main Karatau Fault. The ages of the (possibly ophiolitic) protoliths and the ductile fabrics are not well constrained, but they are plausibly pre-late Riphean. Late Ordovician granites stitch thrusts and folds which deform late Riphean to Llanvirn clastics, preserved beneath a regional Late Devonian angular unconformity. This deformation may be related to a contemporary continental collision NE of the Karatau. Two phases of late Palaeozoic deformation affected the Upper Devonian and Carboniferous carbonate succession. The first phase is related to sinistral transpression along the Karatau Fault System, the second to dextral transpressional reactivation. The combination of these events produced a regional-scale dome-and-basin fold interference pattern. Similar polyphase deformation appears to have affected large areas of Central Asia and was possibly caused by the late Palaeozoic orogenies at Asia’s margins, such as the accretion of Tarim and the East European Craton to Asia, and the closure of the Kazakstan Orocline. Normal faults in the Karatau are related to the formation of the Leontiev Graben, South Turgay Basin and the Yarkand–Fergana Basin in the Early to Mid-Jurassic, during renewed dextral slip along the Karatau/Talas–Fergana Fault. Late Cenozoic deformation is minor, and resulted in the uplift and incision of a Cretaceous–Palaeogene peneplain without a major tectonic overprint. Reversals in the sense of strike-slip dominated transpressive deformation across major fault systems results in transpressive inversion. This represents an ideal process with which to generate overprinting orthogonal fold systems, resulting in classic dome and basin interference patterns on a regional scale.