Urban development increases ?ood risk in cities due to local changes in hydrological and hydrometeorological conditions that increase ?ood hazard, as well as to urban concentrations that increase the vulnerability. The relationship between the increasing urban runoff and ?ooding due to increased imperviousness is better perceived than that between the cyclic impact of urban growth and the urban rainfall via microclimatic changes. The large-scale, global impacts due to climate variability and change could compound these risks. We present the case of a typical third world city – Can Tho (the biggest city in Mekong River Delta, Vietnam) – faced with multiple future challenges, namely: (i) the likely effect of climate change-driven sea level rise, (ii) an expected increase of river runoff due to climate change as estimated by the Vietnamese government, (iii) increased urban runoff driven by imperviousness, and (iv) enhancement of extreme rainfall due to urban growth-driven, microclimatic change (urban heat islands). A set of model simulations were used to construct future scenarios, combining these in?uences. Urban growth of the city was projected up to year 2100 based on historical growth patterns, using a land use simulation model (Dinamica EGO). A dynamic limited-area atmospheric model (WRF), coupled with a detailed land surface model with vegetation parameterization (Noah LSM), was employed in controlled numerical experiments to estimate the anticipated changes in extreme rainfall patterns due to urban heat island effect. Finally, a 1-D/2-D coupled urbandrainage/?ooding model (SWMM-Brezo) was used to simulate storm-sewer surcharge and surface inundation to establish the increase in the ?ood hazard resulting from the changes. The results show that under the combined scenario of signi?cant change in river level (due to climate-driven sea level rise and increase of ?ow in the Mekong) and “business as usual” urbanization, the ?ooding of Can Tho could increase signi?cantly. The worst case may occur if a sea level rise of 100cm and the ?ow from upstream happen together with high-development scenarios. The relative contribution of causes of ?ooding are signi?cantly different at various locations; therefore, detailed research on adaptation are necessary for future investments to be effective.