The current multi-layered interventional approaches to blood safety have dramatically reduced the risk of viral contamination of blood components. Nowadays most of the residual transfusion transmitted infections (TTI) occur as the result of the interval between the time the donor is infected and the moment at which tests are capable of detecting the agent, the so called "window period" which has been considerably reduced by the increased sensitivity of nucleic acid testing (NAT). However, the residual risk of bacterial contamination and the unexpected appearance of some other emerging pathogens, almost every five years, are still of major concern to the public, politicians, regulatory agencies and place immense pressures on the organisations responsible for the provision of safe blood and its components. In view of these bleak scenarios, the use of human blood as a raw biological source is inherently unsafe, and screening/testing alone cannot exclude all the potential human pathogens; hence we need to put in place some sort of safer alternatives and/or additional preventative safety measures. Recently, several substitutes (alternatives) to virtual blood components have been developed and tried. Moreover, various mechanical methods such as cell washing and leukofiltration have been implemented as additional preventative safety measures but with limited success in abrogating the risk of transfusion transmitted cell-associated agents. The most promising approaches, so far, are methods that target pathogen nucleic acids (Methylene blue; Psolaren and Riboflavin UV light treatment). These procedures have undergone considerable in vitro studies to ensure their extremely high safety margins in terms of toxicity to the cells or to the recipients. In essence, while the technology of targeting nucleic acid to stop viral proliferation is common to the above three strategies, in practice these procedures differ in terms of operational, physicochemical and biological characteristics; including the potential impacts of their metabolites and photo-adducts; their effects on the spectrum of pathogens affected and the log reductions in culture infective studies. Accordingly, any strategy that involves addition of an extraneous agent or physicochemical manipulation of blood must balance the benefits of pathogen reduction against the loss or alteration to the cells and plasma functional integrity, short and long term toxicity to the cells and to the recipients, as well as the risk to the personnel involved and the community at large. Moreover, it must be noted that each method will have a different profile of adverse reactions and may differ in terms of the risk to particularly vulnerable groups of patients, requiring in depth clinical trials, while taking into consideration the cost benefit of the final process. Newer diagnostic procedures must be in place to establish the storage stability of products that have undergone pathogen inactivation, in particular tests reflecting the release of platelet-derived cytokines, cellular apoptosis or microvesiculation and their role in immunosupressiveness. This overview aims to provide an update on the continual improvements in blood component safety, in particular using methods that target pathogen nucleic acid. Emphasis is placed on methylene blue light treatment (MBLT) and Intercept or Mirasol PRT systems for platelets and plasma. The status of pathogen reduction of whole blood and red cells is also highlighted, though the progress in this area has been virtually stopped after the finding of antibody development in the clinical trial.