Despite the progress made in screening for blood-transmitted diseases, both the post-infection diagnostic window and the appearance of novel infective agents remain critical issues for the safety of blood transfusions. Viral inactivation methodologies for fresh-frozen-plasma (e.g., treatment with methylene blue or solvent-detergent) are currently being compared, in terms of their activities on viral subtypes and coagulation factors, as well as general toxicity and clinical effects, in order to define the advantages, residual risks and the uncertainties involved in their use.