In the early stages of disease, primary systemic vasculitides often present with non-specific symptoms that make early diagnosis a challenge. The variety of clinical manifestations found in systemic vasculitis is huge, and some manifestations are frequently not clinically overt at first presentation. A logical implication of the often non-specific and sometimes subclinical presentation of vasculitis is that a systematic diagnostic work-up is necessary. This requires a multidisciplinary approach involving the expert opinion of specialists from many disciplines, such as neurology, radiology, respiratory medicine, pathology and microbiology. There are no generally accepted diagnostic criteria for primary systemic vasculitides, and the application of classification criteria as diagnostic criteria is not feasible and may even be misleading. The demonstration of vasculitis on biopsy is still the gold standard for the diagnosis of vasculitis. In cases where biopsies cannot be obtained, surrogate parameters of vasculitis (e.g. glomerular hematuria or mononeuritis multiplex), along with serology and imaging, can support a clinical diagnosis of vasculitis. This review discusses the approach to the diagnosis of central nervous system and pulmonary manifestations of primary systemic vasculitis. These two examples of difficult to diagnose manifestations of vasculitis illustrate the necessity of an interdisciplinary approach to the diagnostic work-up.