This article aims to analyse the efforts made to rationalize pharmaceutical spending in Italy, and, more specifically, the use of off-label drugs. This term commonly indicates the possibility of administering drugs for indications that were not included in the Summary of Product Characteristics (SPC). The article reviews Italian legislation in this field, and analyses its strengths and weaknesses, to propose improvements and additions. Specific focus is dedicated to the recent Avastin®-Lucentis® case, which clearly brought out all the limitations of the current legislation, and which ultimately pushed the Italian legislator to approve a specific law to solve the case (Decree-Law N. 36 of 2014). An in-depth final analysis concerns the recent Constitutional Court’s Judgment N. 151 of 2014. Overall, the most important topics of this paper include the interpretation of the concept of the «therapeutic alternative» (the essential requirement for the use of off-label drugs free of charge, in Italy), how the use of off-label drugs could lead to savings in pharmaceutical sector and, finally, due to the lack of effectiveness of the Italian legislation in the field, possibilities for future improvement that could comply with the relevant European Union legislation.