The interaction between microenvironmental components and tumor cells is bidirectional. Tumor cells and their products are capable of regulating and altering gene expression in nontumor cells residing in or infiltrating into the microenvironment and exert selective pressures on such cells, thereby shaping their phenotype. Conversely, microenvironmental components regulate gene expression in tumor cells thereby directing the tumor into one or several possible molecular evolution pathways, some of which may lead to metastasis. This review summarizes six instances in which the tumor liaises with different components of its microenvironment. These liaisons result, in most cases, in enhanced tumor progression. In these cases (responses of tumor and nontumor cells to microenvironmental stress, the interaction of the tumor with fibroblasts, endothelial cells and macrophages, the formation of the metastatic niche, and the interaction of the tumor with immunoglobulins) the tumor, directly or indirectly, alters the phenotype of its interaction partners thereby enlisting them to promote its progression. Does the tumor need all these pathways to form metastasis? Is there a hierarchy of interactions with respect to impact on tumor progression? These questions remain open. They may be answered by approaches employed in the analysis of hypercomplex systems.