In this study, the authors examine factors underlying payer off-label use reimbursement policies. Updating a study published 14 years ago, presenting the results of the survey of 179 payers administering public (Medicare and Medicaid) pharmacy benefits. The focus is on payers administering pharmacy benefits in the public sector for two reasons: First, transparency; there is a tendency for such payers to reveal more about their decisionmaking processes than payers that exclusively deal with the commercial market. Second, Medicare and Medicaid set the pace in terms of specific policies on off-label use reimbursement, particularly with regard to anti-cancer agents and biologics. The authors investigate the role of primary and secondary sources governing reimbursement of unlabeled indications, including biopharmaceutical compendia, peer-reviewed literature, and clinical practice guidelines. The findings point to the continued variation of off-label use reimbursement policies across payers. Furthermore, the survey data shed light on payer efforts to design off-label use reimbursement strategies, including the use of cost-effectiveness.