In the present study, we performed an integrated proteomics (2DE) and metabolomics (HPLC-MS) investigation to determine the molecular mechanisms underlying cadmium (Cd) tolerance in the halophyte Cakile maritima. Recent physiological reports have documented how C. maritima could accumulate high doses of Cd in roots and shoots, while appearing to be naturally equipped to cope with it, since mild or heavy Cd stress did not alter physiological parameters, including mineral uptake, pigment contents, other than transpiration, water use efficiency and variation of net CO2 assimilation. In the present study, metabolomics and proteomics results highlighted the Cd-dependent up-regulation of thiol compound anabolism, including glutathione and phytochelatin homeostasis, especially in response to elevated Cd stress (100 µM), which allows an intracellular chelation of Cd and its compartmentalization into vacuole. Altered energy metabolism at the triose phosphate level was accompanied by altered accumulation of Calvin cycle intermediates and photorespiration byproducts at high (100 µM), albeit not at mild (25 µM), CdCl2 stress, suggesting that elevated doses of Cd might promote photorespiration. Metabolomics results confirmed proteomics and previous physiological evidence, also suggesting that osmoprotectants betaine and proline, together with plant hormones methyl jasmonate and salicylic acid might be involved in mediating responses to Cd-induced stress. Taken together, from the present study we conclude that C. maritima might represent an ideal candidate for phytoremediation interventions in Cd-contaminated soils.