<p>Cadmium, a significant environmental heavy metal contaminant, poses considerable threats to human health. Cadmium detoxification by microbes, especially yeast, would serve as a potential strategy for coping with cadmium contamination. Based on the screening assay, the non-conventional yeast <i>Wickerhamomyces anomalus</i> BT3 exhibits cadmium stress resistance with a MIC of CdCl₂ exceeding 1000 µM. A prolonged lag phase was observed when BT3 was exposed to &gt; 400 µM cadmium prior to resuming growth in log phase. Thus, suggesting the presence of a cadmium-tolerant genotype in BT3 genomes. Based on the whole genome sequencing analysis, BT3 has a genome size of ~ 14Mbp with 35.0% GC content. Functional gene annotation against the EggNOG and KEGG databases revealed that most of the genes are involved in the genetic translation process. Several key genes potentially involved in cadmium tolerance were identified, including the <i>Yeast cadmium factor (YCF1)</i> gene, which encodes a transporter protein important for cellular homeostasis and detoxification. Genes involved in glutathione synthesis (<i>GSH2</i>) were detected to support the activity. In addition, genes related to oxidative stress response pathways, such as <i>SOD1/2</i>,<i> TRX1</i>,<i> GLRX</i>, and <i>PRX1</i>, were present in BT3 genomes, which promote survival under cadmium-induced oxidative stress conditions. Comparative genome analysis revealed that 2212 gene clusters (36% of BT3 gene clusters) were shared between yeasts. Interestingly, 121 gene clusters were found to be unique to BT3, which predominantly correlated with the gene ontology terms of transmembrane transport activity, integral membrane component, and dimethyl sulfide monooxygenase for the sulfur cycle. Further studies are required to clarify the potential involvement of these unique genetic properties of BT3 in coping with cadmium exposure.</p>