Although the underlying genetic changes have been uncovered in some cases of adaptive evolution, the lack of a systematic study prevents a general understanding of the relative contributions of various mutation types and genetic mechanisms to adaptation. To address this deficiency, we performed 800 generations of laboratory evolution of 3,360 Saccharomyces cerevisiae populations in 252 diverse environments of varying levels of stress, followed by fitness quantification, genome sequencing, and identification and validation of adaptive genomic changes. The yeast adaptations were overwhelmingly fueled by large-effect coding mutations enriched in a small set of adaptive genes overrepresented in signal transduction, transcriptional regulation, transmembrane transport, and chemical homeostasis. Compared with other genes, the adaptive genes have higher expressions, engage in more genetic and protein interactions, cause larger fitness drops when deleted, and are evolutionarily more conserved. These and other findings from the model eukaryote reveal genomic principles and mechanisms of environmental adaptations.