Increasing evidence supports a role for histamine in anxiety and depression. In most studies, histamine and stimulation of the histamine H1 receptor (H1R) or blockade of the histamine H2 receptor (H2R) increase measures of anxiety. In contrast, in most studies histamine reduces depression-like activity, which might be related to effects of histamine on waking. These effects of histamine on anxiety and depression make histamine receptor ligands attractive therapeutic targets. As most studies assessing the potential of histamine receptor ligands on depression did not exclude potential effects of these ligands on locomotor activity, more studies are warranted to determine the exact role of histamine receptor subtypes in depression. The effects of histamine-mediated signaling on anxiety and depression should also be considered in assessments of the potential of histamine H3 receptor (H3R) ligands for conditions characterized by cognitive impairments as well as noncognitive behavioral impairments. Drug Dev. Res. 65:126–132, 2005. © 2005 Wiley-Liss, Inc.