Red blood cell (RBC) transfusions are commonplace in the intensive care unit (ICU) with at least 30% of ICU patients receiving a RBC transfusion at some point during their ICU stay. However, which patients should be transfused and what transfusion trigger(s) should be used remains unclear. RBC transfusion can be associated with adverse effects, but anemia is also associated with worse outcomes. Observational studies and randomized controlled trials (RCTs) have been conducted to try and answer some of the questions surrounding blood transfusion in critically ill patients. The need for blood transfusion and the benefit/risk ratio vary according to individual patient characteristics, including age and comorbidities, so large-scale RCTs in heterogeneous groups of patients may not be the most appropriate tool to investigate these issues; smaller RCTs in carefully defined patient groups may provide more useful information. Rigorous statistical analysis of large, carefully conducted observational studies will also help enhance our evidence-base in this field.