Human emissions of greenhouse gases currently overwhelm the influence of natural drivers on Earth’s climate. The effects of climate change are global; yet many of the most significant impacts are experienced at the regional to local scale. For this reason, a significant proportion of the U.S. National Climate Assessment focuses on the science of climate change, addressing key questions such as: How has human-induced climate change already influenced the weather extremes we experience, from heat waves to hurricanes? Over this century and beyond, how will energy choices and resulting emissions affect temperature and precipitation, extreme events, sea level rise and more? What are the implications for meeting the targets of the Paris Agreement and avoiding dangerous change? And what surprises may the climate system hold over the coming century, as the planet approaches CO2 concentrations last experienced in the Eocene, at an emissions rate unmatched in the paleoclimate record for at least 66 million years? This presentation summarizes what is currently known in these areas and highlights key climate science findings from the Fourth U.S. National Climate Assessment.