Lithium was introduced into contemporary psychiatric therapy in 1949, whereas in 1963 the first article appeared pointing to a prophylactic effect of this ion, preventing the recurrences of affective episodes. In 46 years which have passed, this effect has been confirmed in numerous controlled studies and meta-analyses, and lithium has became a prototype of mood-stabilizing drugs. As for lithium, the property of prevention of suicidal behaviors has been best documented among mood-stabilizing drugs. Neurobiological mechanisms of lithium mood-stabilizing action include, among others, the effect on transmembrane transport, on brain neurotransmitters and intracellular signaling as well as neuroprotective effect. About 1/3 of patients with bipolar affective illness receiving lithium monotherapy experience excellent prophylactic effect (excellent lithium responders). These patients are characterized by the most classical picture and course of the illness. The quality of lithium prophylactic effect has been used as a phenotype for molecular-genetic studies. In 2007, the International Consortium on Lithium Genetics (ConLiGen) has been founded for performing the GWAS (genome-wide association study) in about 2000 of patients receiving lithium prophylaxis. Lithium salts, valproates and carbamazepine were introduced for the treatment and prophylaxis of bipolar affective illness in 1960-1980s and may be regarded as mood-stabilizing drugs of first generation. Since mid-1990s mood-stabilizing properties have been documented for atypical neuroleptic drugs (clozapine, olanzapine, quetiapine, aripiprazole) and for new antiepileptic drug, lamotrigine. These drugs can be classified as mood-stabilizing drugs of second generation.