The potential role for advanced nuclear reactors in U.S. markets is highly uncertain and depends on future technologies, markets, and policies. Using a detailed model of power sector investments and operations, this analysis systematically explores potential drivers and barriers to midcentury advanced nuclear reactor commercialization. Model results suggest that extensive deployment of advanced nuclear technologies would likely require a combination of new policies (especially carbon pricing), innovation in technologies to significantly lower capital and financing costs (likely below $4000/kW), and innovation in business models to enable nonelectricity revenue streams. With policies targeting stringent emissions reductions, the presence of technologies like lower-cost advanced nuclear can reduce compliance costs by over 50%. However, without strong policy support and in a market with low-cost renewables and gas, costs of advanced nuclear reactors would have to decrease substantially from current estimates to make them economically competitive by 2050.