Mammals have been around for about 200 million years, and have developed to be one of the most successful animal groups on the planet. In particular the evolutionary steps during the Paleogene Period have been key in this success story. In this contribution, we discus some of the most important developments in mammal evolution during this time period. After the Cretaceous/Paleogene (K/Pg) extinction (66 million years ago), many ecological niches that were taken by other species became available for the surviving mammals. The first million years after this mass extinction involved a lot of diversification and gave rise to a great diversity of Cenozoic mammals. Additionally, the Paleogene is defined by some of the most intense periods of climate change in the last 100 million years, characterized by hyperthermals such as the Paleocene-Eocene Thermal Maximum (PETM). These climate-events probably were important drivers of evolution in the Paleogene.