Acute cytokine release syndromes are associated with some therapeutic antibodies in man, leading to a spectrum of clinical signs from nausea, chills and fever to more serious dose limiting hypotension and tachycardia. When anticipated this syndrome is typically manageable, however this adverse reaction recently became headline news when a massive and unexpected cytokine release syndrome occurred within a few hours of dosing six healthy volunteers with a therapeutic antibody, putting their lives at risk due to multiple organ failure. Preclinical studies did not predict this adverse event, emphasising the need to compare the relative potency of the product in man and the chosen toxicology species, so that additional margins of safety can be applied when conducting first in man (FIM) studies if there is uncertainty over the predictability of the toxicology species. In vitro human PBMC and whole blood cultures may be useful for predicting cytokine release. However since cytokine release arises through at least two distinct mechanisms, it should be emphasised that the utility of these in vitro methods needs to be established for each antibody product.