Cereals are a major dietary source of the toxic metal cadmium (Cd). Reducing Cd accumulation in cereal crops such as wheat (Triticum aestivum) is important for food safety and human health. In this study, we show that three diverse cultivars of wheat had a high Cd translocation from roots to shoots, similar to a rice (Oryza sativa) cultivar possessing a nonfunctional tonoplast Cd transporter OsHMA3. We investigated the function of TaHMA3 genes in wheat. Three TaHMA3 genes were identified in wheat, all of which encode tonoplast-localized proteins. However, heterologous expression of TaHMA3 genes in yeast showed no transport activities for Cd, which likely explains the low Cd sequestration in wheat roots and subsequently the high Cd translocation to wheat shoots. To increase Cd sequestration in wheat roots, we overexpressed a rice functional OsHMA3 gene in wheat driven by a strong constitutive Ubiquitin promoter. Overexpression of the OsHMA3 gene decreased root-to-shoot Cd translocation in wheat by nearly 10-fold and Cd accumulation in wheat grain by 96%. The results suggest that high Cd translocation is a common trait in wheat caused by a loss of the Cd transport function of TaHMA3 proteins. Transgenic wheat overexpressing a functional OsHMA3 gene offers a highly effective solution to decrease Cd accumulation in wheat grain.