Granulomatosis with polyangiitis and microscopic polyangiitis are two autoimmune diseases characterised by necrotising small-vessel vasculitis and presence of antineutrophil cytoplasm autoantibodies (ANCA). Current immunosuppressive regimes that combine cyclophosphamide and glucocorticoids have dramatically improved the outcome for these patients. However, these treatments are associated with toxic effects and do not lead to permanent remission in the majority of cases. Newer approaches have been sought during the last 15 years, with improvement in medication protocols and inclusion of novel therapies. This review develops on seven clinical conundrums of evidence-based therapeutic strategies for ANCA-vasculitis, posed as questions on aspects such as the role of established drugs in both remission induction and maintenance: glucocorticoids (and its duration), oral cyclophosphamide, methotrexate, TNF-α blockers, plasma exchange, mycophenolate mofetil, plus one related to newer developments in treatment with agents blocking the complement system and the possible role of sequential or combined therapies, mainly directed against B cells.