The incidence of tuberculosis (TB) disease in the United States has stabilized, and additional interventions are needed to make progress toward TB elimination. But the impact of such interventions depends on local demography and heterogeneity in populations at risk. Using state-level individual-based TB transmission models, calibrated to California, Florida, New York, and Texas, we modeled two TB interventions: (i) Increased targeted testing and treatment (TTT) of high-risk populations, including people who are non-US-born, diabetic, HIV-positive, homeless, or incarcerated; and (ii) Enhanced TB contact investigation (ECI), including higher completion of preventive therapy. For each intervention, we projected reductions in active TB incidence over 10 years (2016-2026) and numbers needed to screen and treat to avert one case. TTT delivered to half of the non-US-born adult population could lower TB incidence by 19.8%-26.7% over ten years. TTT delivered to smaller populations with higher TB risk (e.g., HIV-positive, homeless) and ECI were generally more efficient, but had less overall impact on incidence. TTT targeted to smaller, highest-risk populations, and ECI can be highly efficient; however, major reductions in incidence will only be achieved by also targeting larger, moderate-risk populations. Ultimately, to eliminate TB in the US, a combination of these approaches is necessary.