Transfusion has become extremely safe but can still be associated with adverse reactions. Some adverse reactions can be mitigated by applying measures to donor selection, the process of separating blood components as well as hospital-based procedures consisting in matching the donor and the recipient; special attention is given to optimizing the best fit between the component and the beneficiary, which is not only an immuno-hematological challenge (fresh versus old blood, testing for certain viruses such as CMV, parvovirus B19, etc.). Considerable progress has also been achieved to strengthen the overall quality and safety of the whole transfusion chain. Guidelines and recommendations have resulted in substantial progress, and the recent revisiting of patients as part of a more holistic approach has enabled blood management programs to be created. Such programs, when wisely applied in a context of optimal blood use, reinforce patient safety; they enhance hospital recognition of transfusion and hemovigilance specialists as useful players acting in the interests of patients in full compliance with hospital budgets. This review considers the step-by-step processes that reinforce transfusion safety and identifies hurdles that cannot yet be properly addressed; it proposes steps for further progress, in light of personalized medicine.