Relative sea level rise (RSLR) due to climate change and geodynamics represents the main threat for the survival of Venice, emerging today only 90 cm above the Northern Adriatic mean sea level (msl). The 25 cm RSLR occurred over the 20th century, consisting of about 12 cm of land subsidence and 13 cm of sea level rise, has increased the flood frequency by more than seven times with severe damages to the urban heritage. Reasonable forecasts of the RSLR expected to the century end must be investigated to assess the suitability of the Mo.S.E. project planned for the city safeguarding, i.e., the closure of the lagoon inlets by mobile barriers. Here we consider three RSLR scenarios as resulting from the past sea level rise recorded in the Northern Adriatic Sea, the IPCC mid-range A1B scenario, and the expected land subsidence. Available sea level measurements show that more than 5 decades are required to compute a meaningful eustatic trend, due to pseudo-cyclic 7–8 year long fluctuations. The period from 1890 to 2007 is characterized by an average rate of 0.12 ± 0.01 cm/year. We demonstrate that linear regression is the most suitable model to represent the eustatic process over these 117 year. Concerning subsidence, at present Venice is sinking due to natural causes at 0.05 cm/year. The RSLR is expected to range between 17 and 53 cm by 2100, and its repercussions in terms of flooding frequency are associated here to each scenario. In particular, the frequency of tides higher than 110 cm, i.e., the value above which the gates would close the lagoon to the sea, will increase from the nowadays 4 times per year to a range between 20 and 250. These projections provide a large spread of possible conditions concerning the survival of Venice, from a moderate nuisance to an intolerable aggression. Hence, complementary solutions to Mo.S.E. may well be investigated.