The evolution of multicellularity was a major transition in evolution and set the stage for unprecedented increases in complexity, especially in land plants and animals. Here we explore the genetics underlying a de novo origin of multicellularity in a microbial evolution experiment carried out on the green alga Chlamydomonas reinhardtii. We show that large-scale changes in gene expression underlie the transition to a multicellular life cycle. Among these, changes to genes involved in cell cycle and reproductive processes were overrepresented, as were changes to C. reinhardtii-specific and volvocine-specific genes. These results suggest that the genetic basis for the experimental evolution of multicellularity in C. reinhardtii has both lineage-specific and shared features, and that the shared features have more in common with C. reinhardtii’s relatives among the volvocine algae than with other multicellular green algae or land plants.