Mental disorders are highly prevalent and often difficult to diagnose. There is a significant gap between advances in their pharmacotherapy and the present lack of objective biologic tests for diagnosis. The special complexity of diagnosis in psychiatry is related to the absence of objective diagnostic "gold standards", co-morbidity, heterogeneity and equifinality, quantitative trait loci, and locus heterogeneity. Here, we review recent findings relating to diagnostic, pathophysiological, and linkage markers for mood disorders at the biochemical level involving monoamine neurotransmitters, hormones, and signal-transducing G proteins. Identification of biological diagnostic markers could enable segregating mood disorders to several biologically different subtypes. New-era methods and strategies involving genomics, proteomics, multi-marker approach and single nucleotide polymorphisms have the potential to revolutionize future diagnosis in psychiatry.