The objective of systematic reviews of the efficacy and safety of interventions is to determine in an unbiased and objective manner whether a proper balance between risks and benefits exists. However, systematic reviews including many Cochrane reports often get criticized for having an overly narrow focus on randomized controlled trials leading to results that have low applicability and do not adequately reflect the underlying risk-benefit profiles. The objective of this paper is to encourage the discussion on two important issues frequently covered inadequately in Cochrane reports: the assessment of adverse effects and the applicability of results. It also strives to outline approaches for improving the comprehensiveness and usability of Cochrane reports by including observational evidence for adverse effects assessment on a regular basis and by putting more emphasis on factors that determine the applicability of findings.