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The Indonesian Throughflow (ITF) is an important component of the upper cell of the global overturning circulation that provides a low-latitude pathway for warm, fresh waters from the Pacific to enter the Indian Ocean. Variability and changes of the ITF have significant impacts on Indo-Pacific oceanography and global climate. In this paper, the observed features of the ITF and its interannual to decadal variability are reviewed, and processes that influence the centennial change of the ITF under the influence of the global warming are discussed. The ITF flows across a region that comprises the intersection of two ocean waveguides—those of the equatorial Pacific and equatorial Indian Ocean. The ITF geostrophic transport is stronger during La Niñas and weaker during El Niños due to the influences through the Pacific waveguide. The Indian Ocean wind variability associated with the Indian Ocean Dipole (IOD) in many years offsets the Pacific ENSO influences on the ITF geostrophic transport during the developing and mature phases of El Niño and La Niña through the Indian Ocean waveguide, due to the co-varying IOD variability with ENSO. Decadal and multi-decadal changes of the geostrophic ITF transport have been revealed: there was a weakening change from the mid-1970s climate regime shift followed by a strengthening trend of about 1Sv every 10 year during 1984–2013. These decadal changes are mostly due to the ITF responses to decadal variations of the trade winds in the Pacific. Thus, Godfrey’s Island Rule, as well as other ITF proxies, appears to be able to quantify decadal variations of the ITF. Climate models project a weakening trend of the ITF under the global warming. Both climate models and downscaled ocean model show that this ITF weakening is not directly associated with the changes of the trade winds in the Pacific into the future, and the reduction of deep upwelling in the Pacific basin is mainly responsible for the ITF weakening. There is a need to amend the Island Rule to take into account the contributions from the overturning circulation which the current ITF proxies fail to capture. The implication of a weakened ITF on the Indo-Pacific Ocean circulation still needs to be assessed.