Blood transfusion is an important aspect of medicine and patient safety plays a very important role. A myriad of blood-borne infectious agents can be potentially transmitted through transfusion of blood and blood products donated by apparently healthy and asymptomatic donors. The diversity of infectious agents includes human immunodeficiency viruses 1 and 2, hepatitis B virus, hepatitis C virus, malaria, syphilis, human T-lymphotropic virus types 1 and 2 and in certain circumstances, hepatitis A virus, cytomegalovirus, parvovirus B19, and many more. Besides the established viral, bacterial, and parasitic diseases, novel agents have now appeared and are still emerging as potential threats in transfusion medicine. While transmission of prion protein causing variant Creutzfeldt–Jakob disease is of prime concern in countries like the United Kingdom (UK), bacterial infections and viruses such as Dengue and Chikungunya are of prime concern in the Asian region. Transfusion centers employ three levels of screening to ensure blood safety: donor screening interventions to exclude high-risk donors, testing for infectious markers by serology, nucleic acid testing methods and processing technologies like leukoreduction, use of diversion pouch in blood collection, and use of aseptic blood collection technique. Implementing new technologies like pathogen reduction to destroy/inactivate pathological substances in blood components using chemicals or UV lights coupled with expanding testing for emerging diseases will certainly increase the safety of blood. The ultimate aim is to minimize the risks of transfusion-transmitted infection during the window period of infectious agent in a cost-effective and efficient manner. Although considerable effort and resources have been invested, no single technique is yet effective and we are far from achieving zero risk. The main challenges are faced by developing countries due to limited resources.