Wheat, one of the most broadly cultivated and consumed food crops worldwide, can accumulate high Cd contents in their edible parts, which poses a major hazard to human health. Cd accumulation ability differs among varieties in wheat, but the underlying molecular mechanism is largely unknown. Here, key genes responsible for Cd accumulation between two contrasting wheat genotypes (low-Cd accumulation one L17, high-Cd accumulation one H17) were investigated. Total 1269 were differentially expressed genes (DEGs) in L17 after Cd treatment, whereas, 399 Cd-induced DEGs were found in H17. GO-GO network analysis showed that heme binding was the most active GO, and metal binding was the second one that associated with other GOs in response to Cd stress in both genotypes. Pathway-pathway network analysis showed that phenylpronanoid biosynthesis and glutathione metabolism were the top pathways in response to Cd stress in both genotypes. Furthermore, we found that DEGs related to ion binding, antioxidant defense mechanisms, sulfotransferase activity, and cysteine biosynthetic process were more enriched in L17. In conclusion, our results not only provide the foundation for further exploring the molecular mechanism of Cd accumulation in wheat but also supply new strategies for improving phytoremediation ability of wheat by genetic engineering.