Therapy of tumor progression and the metastatic disease is the biggest challenge of clinical oncology. Discovery of the diverse molecular pathways behind this complex disease outlined an approach to better treatment strategies. The development of combined cytotoxic treatment protocols has produced promising results but no breakthrough in the clinical management of metastatic disease. The multiple - specific and non-specific pathways and cellular targets of tumor progression are outlined in this review. Such an approach, individually designed for various cancer types, may have a better chance to treat or even cure cancer patients with progressive disease.