The Head Start program, launched in 1965 and targeted to children from disadvantaged backgrounds, remains the largest early childhood care and education (ECE) program in the United States and the only one deployed at the federal level. As such, the Head Start literature spans several decades and now allows for synthesis of findings from different contexts, time periods, and research designs. This paper provides a comprehensive assessment of the rigorous evidence measuring Head Start’s effects on children, their families, and society. The focus is on how (1) the contrast between program and counterfactual conditions, (2) takeup of the program among eligible populations, and (3) treatment-effect heterogeneity inform interpretation and applicability of key findings. The paper presents implications of the evidence for the modern-day Head Start program and an adjacent, policy-relevant research agenda.