Through systematically exploring the fitness landscape in a genome-wide manner, genome-scale engineering can test multiple hypotheses in parallel and overcome our limited knowledge of biocomplexity. However, existing methods to create a genome-wide deletion library in yeast require years and many researchers. Here we report a CRISPR/Cas9 and homology-directed repair assisted genome-scale engineering (CHAnGE) method that enables generation of a genome-wide library of yeast gene disruption mutants each with a defined 8 nucleotides removal by a single researcher within a month. Such unprecedented precise and small deletions minimize the risk of disrupting overlapping genomic features and chromatin structures. We validated CHAnGE by identification of single disruption mutants conferring 5~7 fold improved tolerance to different growth inhibitors including acetic acid and furfural in a genome-wide manner (targeting 6459 genes). We further iterated CHAnGE for directed evolution of yeast genomes, achieving an additional 3~8 fold improvement. Finally, we demonstrated the genome-editing capability of CHAnGE at a single-nucleotide resolution and provided preliminary evidence that CHAnGE will work in mammalian cells.