Cadmium (Cd) is among the world’s major health concerns, as it renders soils unsuitable and unsafe for food and feed production. Phytoremediation has the potential to remediate Cd-polluted soils, but efforts are still needed to develop a deep understanding of the processes underlying it. In this study, we performed a comprehensive analysis of the root response to Cd stress inA. thaliana, which can phytostabilize Cd, and inA. halleri, which is a Cd hyperaccumulator. Suitable RNA-seq data were analyzed by WGCNA to identify modules of co-expressed genes specifically associated with Cd presence. The results evidenced that the genes of the hyperaccumulatorA. hallerimostly associated with the Cd presence are finely regulated (up- and downregulated) and related to a general response to chemical and other stimuli. Additionally, in the case ofA. thaliana, which can phytostabilize metals, the genes upregulated during Cd stress are related to a general response to chemical and other stimuli, while downregulated genes are associated with functions which, affecting root growth and development, determine a deep modification of the organ both at the cellular and physiological levels. Furthermore, key genes of the Cd-associated modules were identified and confirmed by differentially expressed gene (DEG) detection and external knowledge. Together, key functions and genes shed light on differences and similarities among the strategies that the plants use to cope with Cd and may be considered as possible targets for future research.