Background: Dissemination of cancer cells from the primary tumor and establishment of therapy-resistant distant metastases is the most common cause of human cancer deaths. The primary tumor consists of a heterogeneous population of cancer cells that have to overcome activity of the immune system, insufficient delivery of nutrients and oxygen, chemotherapy, radiotherapy etc. that lead to the selection of resistant and plastic cancer cells. Another selection pressure during metastatic spread gives rise to resistant subpopulations of cells, capable of surviving and proliferating in the hostile microenvironment of distant tissues. Aim: In this article, individual steps of the metastatic cascade are described as well as the mechanisms and signaling pathways that cancer cells use to deal with them. Metastatic process is generally inefficient and only very few cells released from the primary tumor develop into metastases. This success is enabled by pro-metastatic mutations, accumulated due to the selection pressure and also by cooperation of non-transformed cells that secrete supporting factors. Conclusion: Recent advances in research provide deeper insights into the complex processes that lead to formation and dissemination of cancer cells. Deciphering the key points of metastatic cascade and principles of its regulation will perhaps lead to development of efficient therapeutics targeting metastatic cells.