Bipolar is a severe psychiatric disorder which ethiopathogenesis remains unclear. Despite a clearly established heritability, genetic studies have failed to elucidate the underlying mechanism of bipolar disorder, most likely due to the contributing role of environmental factors in the genesis of the disease. Environmental factors have been consistently described to induce immuno-inflammation dysfunction, which are also known to play a role in the pathogenesis of bipolar disorders as due to the combined actions of small effects in many different genes interacting with environmental factors). Several mechanisms might explain the proinflammatory processes observed in bipolar disorder. Emerging evidence support the pathophysiological role of Human Endogenous Retroviruses, which reactivation (normally silenced), can be induced by infectious agents during pregnancy, early childhood and/or adolescence. Neurotoxic effects and inflammatory state are induced, which might in turn and after a prodromal phase, trigger acute mood episodes. The present paper reviews the role of the immuno-inflammatory processes as key contributors to the bipolar disorders pathophysiology, the evidence supporting immuno-genetic predisposition, background, and the the possible implications of retroviruses reactivation in the pathogenesis of bipolar disorder.