Despite of advances in pharmacological and non-pharmacological treatments, bipolar disorder often entails multiple relapses and impaired psychological functioning. The extent to which modern treatments have influenced the natural course of a mental disorder is uncertain. Prediction of the course and outcome of bipolar disorders continues to be challenging, despite the multiple research efforts worldwide. Due to a lack of laboratory diagnostic tests and biomarkers, psychiatric interview and examination provide the basis for outcome prediction. While considered to have more favorable prognosis than schizophrenia, it is not uncommon for bipolar disorder to include persisting alterations of psychosocial functioning. Although long-term symptomatic remission does not guarantee functional recovery, it may have a favorable impact on long-term overall prognosis. The high degree of treatment resistance in patients with bipolar disorder highlights the need to develop better identification of outcome predictors, prognosis and treatment intervention, designed to reverse or prevent this illness burden. This review summarizes the main factors involved in predicting the course and outcome of bipolar disorder.