In the 1990s Post-weaning, multi-systemic wasting syndrome (PMWS) emerged in N. America and Europe as a major disease problem with significant welfare and economic consequences for pig producers. The disease, characterised by wasting, respiratory, enteric and lymphoid system problems in pigs of 4-16 weeks of age, has since spread so that today it has a global distribution. PCV-2 is consistently associated with PMWS, is more abundant in association with PMWS and is considered by many to be the causative agent of the syndrome. However, several lines of evidence indicate that PCV-2 is necessary but not sufficient to cause the full range of clinical signs associated with PMWS, suggesting the involvement of an as yet unidentified factor or factors. The process of identifying unknown agents and their respective roles in the pathogenesis of complex syndromes now has an ever broadening spectrum of analytical techniques available. Immune phenotyping, cytokine responses, micro-array profiling, and proteomics are just some of the techniques available. This paper describes the philosophy and the application of these and classical techniques in an integrated, holistic manner to the problem of PMWS and circoviruses, by examination of samples collected from a prospective, clinical case-control study, and discusses some of the preliminary findings in relation to the efforts to understand the aetiopathogenesis of PMWS.