Cadmium (Cd) has become one of the most important environmental pollutants in the world, derived from natural and industrial sources, which is known to be accumulated in the human body, producing serious health effects. On the other hand, Selenium (Se) is an essential element for mammals, which is well known for its antagonistic interaction against Cd toxicity, such as the prevention of oxidative stress induced by this element. For this reason, the use of complementary analytical methods to study the homeostasis of metals, "traffic" between different organs and massive information about metabolites altered by the exposure is of great interest. To this end, a metabolomic workflow based on the use of direct infusion mass spectrometry (DIMS) and gas chromatography mass spectrometry (GC-MS) was applied in mice serum. On the other hand, metals homeostasis and traffic between different organs and serum of mice exposed to Cd and Se, have been evaluated by determining the concentration of metals by inductively coupled plasma mass spectrometry. This work, demonstrate for the first time that Cd exposure causes a decrease of all the elements studied in lung except itself. On the other hand, Se provokes As trafficking from metabolically less active organs (brain, lung and testes) to others with greater metabolic activity (kidney), which also facilitates its excretion. Moreover, when mice are only exposed to Se, it provokes the accumulation of almost all the elements in kidney, except Cd that increases also in liver and brain. However, when both elements are simultaneously administered, Se increases Cd concentration in all the organs except in serum and especially in testis. On the other hand, important metabolic alterations have been detected in the energy and amino acid metabolism, as well as degradation of phospholipidic membranes, and in free fatty acids. In summary, the results show the high potential of the combined use of organic and inorganic mass spectrometry to establish Cd and Se interaction, the biological impairments caused and to provide information about metals traffic and metabolomic changes in exposure experiments.