U.S. population health faces many challenges, including stagnating and even declining life expectancy, and widening health disparities. Against this backdrop, I will discuss the role of selection in the trend of health disparities, evaluate the “Deaths of Despair” narrative, and analyze the cohort health trend. The first study addresses the dynamics of smoking initiation and cessation and how they may contribute to the widening educational gap in smoking prevalence. The second study directly investigates despair as a determinant of death and the temporal variation and racial heterogeneity therein. The third study investigates whether the increasing morbidity and mortality among middle-aged and young-old Americans since the turn of the century has been extended to younger cohorts. I explore conditions from birth to the present by investigating the nutrition, health, socioeconomic, psychological, and bio-behavioral factors throughout the life course across multiple birth cohorts. I probe both protective resources that might advantage recent cohorts and risk factors that might disadvantage recent cohorts. By doing so, we gain a preliminary but plausible account of what may or may not contribute to adverse cohort health trends, and what disadvantages may offset advantages to which recent cohorts are subjected. To wrap up, I will discuss the policy implications from these three studies.