Atherothrombosis is no longer considered solely a disorder of lipoprotein 
accumulation in the arterial wall. Rather, the initiation and progression of 
atherosclerotic lesions is currently understood to have major inflammatory 
influences that encompass components of both the innate and acquired immune 
systems. Promising clinical data for 'upstream' biomarkers of inflammation such 
as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive 
protein, observations regarding cholesterol crystals as an activator of the 
IL-1β generating inflammasome, and recent Mendelian randomization data for the 
IL-6 receptor support the hypothesis that inflammatory mediators of 
atherosclerosis may converge on the central IL-1, tumour necrosis factor 
(TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory 
approaches to vascular protection can be categorized into two broad groups, 
those that target the central IL-6 inflammatory signalling pathway and those 
that do not. Large-scale Phase III trials are now underway with agents that lead 
to marked reductions in IL-6 and C-reactive protein (such as canakinumab and 
methotrexate) as well as with agents that impact on diverse non-IL-6-dependent 
pathways (such as varespladib and darapladib). Both approaches have the 
potential to benefit patients and reduce vascular events. However, care should 
be taken when interpreting these trials as outcomes for agents that target IL-6 
signalling are unlikely to be informative for therapies that target alternative 
pathways, and vice versa. As the inflammatory system is redundant, compensatory, 
and crucial for survival, evaluation of risks as well as benefits must drive the 
development of agents in this class.