The electrochemical reactivity of tailor-made CuO powders prepared according to a new low-temperature synthesis method was studied by a combination of transmission electron microscopy (TEM) and electrochemical techniques. All the processes involved during cycling were successfully identified. We show that the reduction mechanism of CuO by lithium involves the formation of a solid solution of Cu(1-x)(II)Cu(x)(I)O(1-x/2)0 less than or equal to x less than or equal to 0.4, a phase transition into Cu2O, then the formation of Cu nanograins dispersed into a lithia matrix (Li2O) followed by the growth of an organic-type coating. This one is responsible for the extra capacity observed on the voltage vs. composition curve. During the subsequent charge, the organic layer vanishes first, and then the Cu grains are partially or fully oxidized with a concomitant decomposition of Li2O. The formation of Li2O and Cu nanograins and then the one of Cu, CuO, and Cu2O nanograins on the first discharge and subsequent charge, respectively, were identified by high-resolution TEM studies. These results enabled a better understanding of the processes governing the reactivity of 3d metal oxides vs. lithium down to 0.02 V.