Solid tumour therapy with chemotherapeutic drugs is hampered by a number of factors resulting in poor results and failure of initially promising drugs. From the application of Tumour Necrosis Factor α in the melphalan-based Isolated Limb perfusion some lessons could be learned. Most importantly, combination of treatment approaches, certainly when multiple targets are involved, increases the effectiveness of the therapy. Clinical outcome may improve dramatically when the tumour pathophysiology is changed in such a way that co-administered chemotherapeutics are more active or are capable of reaching the tumour cells better. Here some of the methodologies and drug combinations which improve solid tumour therapy through acting on the tumour pathophysiology are discussed.