Trace greenhouse gases are a fundamentally important component of Earth's global climate system sensitive to global change. However, their concentration in the pre-Pleistocene atmosphere during past warm greenhouse climates is highly uncertain because we lack suitable geochemical or biological proxies. This long-standing issue hinders assessment of their contribution to past global warmth and the equilibrium climate sensitivity of the Earth system (E(ss)) to CO(2). Here we report results from a series of three-dimensional Earth system modeling simulations indicating that the greenhouse worlds of the early Eocene (55 Ma) and late Cretaceous (90 Ma) maintained high concentrations of methane, tropospheric ozone, and nitrous oxide. Modeled methane concentrations were four- to fivefold higher than the preindustrial value typically adopted in modeling investigations of these intervals, even after accounting for the possible high CO(2)-suppression of biogenic isoprene emissions on hydroxyl radical abundance. Higher concentrations of trace greenhouse gases exerted marked planetary heating (> 2 K), amplified in the high latitudes (> 6 K) by lower surface albedo feedbacks, and increased E(ss) in the Eocene by 1 K. Our analyses indicate the requirement for including non-CO(2) greenhouse gases in model-based E(ss) estimates for comparison with empirical paleoclimate assessments, and point to chemistry-climate feedbacks as possible amplifiers of climate sensitivity in the Anthropocene.