Cretaceous through Paleogene dominantly calc-alkaline magmatism in the Lake Clark region, southwestern Alaska, can be divided into three main periods of activity based on previous work and new ⁴⁰Ar/³⁹Ar and U-Pb geochronology. These episodes follow a protracted history of arc magmatism related to the Talkeetna arc. The first episode is Albian based on new ⁴⁰Ar/³⁹Ar dates from hornblende in dikes cutting the Tlikakila complex of 101–97 Ma. These rocks have relatively flat REE patterns and Th/Nb values lower than typical arc rocks but higher than average mid-ocean ridge basalt (MORB). These data are consistent with rift-related magmatism in a region that had previously experienced arc magmatism. The second episode is represented by a granodiorite with a SHRIMP U-Pb zircon age of 64.5 ± 0.9 Ma and is similar to widespread 70–60 Ma volcanic rocks to the west of the study area. These calc-alkaline rocks are enriched in the light REE and have high Th/Nb values. They were generated during northward subduction of the Kula plate beneath Alaska. The Eocene episode is also calc-alkaline with enriched light rare earth element (REE) and high Th/Nb values. ⁴⁰Ar/³⁹Ar equilibria in 100 Ma dikes were reset at 44–42 Ma, and biotite from a rhyolite indicates an eruptive age of 43.0 ± 0.2 Ma. These 43 Ma rocks formed during initiation of Aleutian magmatism on the continent in response to north or northwest subduction of the Pacific plate and may be related to a change in the direction or velocity of subduction at this time.