Sympathetic nervous system activation is a hallmark of several conditions associated with an adverse prognosis, including hypertension and the metabolic syndrome. Proposed mediators of increased sympathetic drive include hyperinsulinaemia, leptin, NEFAs (non-esterified fatty acids), pro-inflammatory cytokines, baroreflex impairment and others. The role of NEFAs appears to be of particular importance given the increased levels observed in human obesity and the experimental results linking the NEFA-induced pressor response to sympathetic activation. Findings from human studies have yielded conflicting results with regards to a sympathetically mediated association between NEFAs and elevated arterial blood pressure. In the present issue of Clinical Science, Florian and Pawelczyk present some interesting results obtained from a small number of healthy normotensive lean volunteers who were exposed to NEFA infusion and cardiovascular and sympathetic monitoring using state of the art methodology that appears to be in support of such a link. However, several methodological and conceptual considerations need to be taken into account when interpreting the results from this study. Put into perspective, the case for a substantial sympathetically mediated pressor response to NEFA infusion does not appear to be a very strong one.