Genome rearrangements resulting in copy number variation (CNV) and loss of heterozygosity (LOH) are frequently observed during the somatic evolution of cancer and promote rapid adaptation of fungi to novel environments. In the human fungal pathogen Candida albicans, CNV and LOH confer increased virulence and antifungal drug resistance, yet the mechanisms driving these rearrangements are not completely understood. We recently identified an extensive array of long repeat sequences (65-6499 bp) that are associated with CNV, LOH, and chromosomal inversions in this organism. Here, we describe the rapid acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. The CNVs contain several genes that encode potential drug resistance/drug tolerance factors. Subsequent removal of the antifungal drug can lead to a dramatic loss of the CNV and reversion to the progenitor genotype and drug susceptibility phenotype. These findings support a novel mechanism for the rapid acquisition of antifungal drug resistance and provide a genomic basis for the heterogeneity observed in clinical settings.