A renewed concern with social factors has emerged in global public health, spearheaded by the World Health Organization's Commission on Social Determinants of Health. The coming decade may see significant health gains for disadvantaged populations if policies tackle the social roots of health inequities. To improve chances of success, global action on social determinants must draw lessons from history. This article reviews milestones in public health action on social determinants over the past 50 years. The goal is to bring into sharper focus the persistent challenges faced by social determinants agendas, along with distinctive opportunities now emerging. The historical record highlights the vulnerability of health policy approaches incorporating social determinants to resistance from entrenched interests. The Commission on Social Determinants of Health can consolidate political support by building collaborative relationships with policymakers in partner countries. However, this strategy must be complemented by engaging civil society constituencies. Historically, successful action on social determinants has been spurred by organized civil society demand.