The processes of inflammation that are necessary for effective host defence against infection also drive the pathogenesis of many non-infectious diseases. Platelet activation is a causal and sometimes major component of these inflammatory processes, and they are involved in both innate and adaptive immunity. However, the activation of platelets in these inflammatory contexts is often distinct to the other requisite role of platelets during haemostasis. Interestingly, endogenous nucleotides and nucleosides that are released extracellularly as components of a dynamically changing “purinome” act to orchestrate both inflammatory and haemostatic responses through the activation of platelets. How platelet activation by these purines occurs in the context of inflammation is discussed here, and the opportunities of targeting platelet purinergic receptors for the development of novel anti-inflammatory drugs is debated.