This chapter explores the immunological and inflammatory functions of platelets, particularly in blood transfusions. Traditionally recognized for their role in hemostasis, platelets have been shown to actively engage with the immune system, partly through receptors such as Toll-like receptors (TLRs) and biological response modifiers (BRMs). They release various bioactive molecules, such as cytokines, extracellular vesicles (EVs), and microRNAs, which play a role in inflammation and immunity. These molecules, including those released during platelet storage, can lead to transfusion-related adverse events. Studies link TLR activation, particularly TLR4 and TLR9, with platelet-driven inflammation, while identifying HMGB1 and mitochondrial DNA (mtDNA) as key mediators in immune responses. Storage lesions, which refer to changes that occur in platelets during preparation and storage, further affect transfusion safety and effectiveness. Platelet additive solutions, cold storage, and pathogen reduction technologies are examined as methods to mitigate storage-related inflammation and improve transfusion outcomes. These processes, however, have limitations and require further research aimed at optimizing platelet storage and handling, minimizing adverse events, enhancing platelet transfusion yield, and improving transfusion practices for various patient needs.