Phytoremediation has gained considerable attention as a low-cost and eco-friendly solution for remediating heavy metal soil contaminants such as cadmium (Cd). However, a reliable method has yet to be established because of the lack of understanding of the accumulation mechanism, as was the case in the Cd/Zn hyperaccumulator plant Arabidopsis halleri ssp. gemmifera. Here, a comprehensive analysis of A. halleri ssp. gemmifera root RNA sequences provides a concrete model of Cd uptake, transport, and responses. Three-month-old seedlings were exposed to 5 µM CdCl2 for two hours to examine their early responses. To alleviate Cd toxicity, root cells activated ABCG transporters (ABCG29, ABCG8, and ABCG12) to efflux Cd into the apoplast or xylem for translocation. The remaining intracellular Cd was bound in complexes with HIPP, glutathione, and some was transported into the vacuole (ABCC1, ABCC2, and MTPC3). Cell wall modification to prevent Cd entry or stabilize Cd was indicated by increased transcription of lignin biosynthesis-related genes. Transporters and ion channels (HMAs and CNGC13) were found to regulate cellular Cd uptake. Both ROS and hormones, such as ABA, ethylene, and JA, also act as signaling molecules responsible for activating the MAPK pathway and regulating gene transcription. In addition, it was revealed that most of the uptake, transport, and response mechanisms between Cd and Zn in A. halleri ssp. gemmifera were different. Altogether, this study provides insights into A. halleri ssp. gemmifera response to Cd uptake, which may aid in developing an effective phytoremediation strategy and commercializing the process of soil Cd removal.