BACKGROUND: Depression is a therapeutic challenge with bipolar disorder (BD) patients and remains a major contributor to disability, comorbidity, and premature mortality. Efficacy and safety of antidepressants for this indication remain particularly controversial and optimally safe and effective treatment of bipolar depression remains uncertain. METHOD: We summarized selected research findings on treatment of depression in BD aimed at supporting practical guidelines for clinical treatment involving antidepressants. RESULTS: Growing research evidence indicates that antidepressants are probably effective in bipolar depression and possibly not less than in major depressive disorder (MDD). Tolerability of antidepressant treatment is greater with type II BD (BD-2) than with type I (BD-1), particularly when antidepressants are combined with a mood-stabilizer or antipsychotic. For bipolar depression preferred antidepressants are serotonin-reuptake inhibitors (SRIs) and bupropion given in moderate doses for limited times. CONCLUSIONS: Optimal treatment of depression requires further investigation, particularly for long-term maintenance. Nevertheless, treatment for acute depressive episodes can usefully and safely include some antidepressants in moderate doses for limited duration, best combined with lithium, some anticonvulsants or certain atypical antipsychotics, and more safely with BD-2 than BD-1 with close clinical supervision.