Metastatic spread is an inefficient process which requires generation of supportive microenvironments in which cancer cells can survive, proliferate and escape from immune attack. These niches are induced by systemic and locally produced factors and establish a tumor-supportive and immune suppressive environment which is molecularly and functionally different from the niche at the primary site. Tumor dormancy may result if the niche is not sufficiently supportive/protective. Co-evolution of cancer cells and the surrounding microenvironment creates a large number of such dynamic niches, and we are just beginning to elucidate the complexity of these interactions and their tissue-specific differences. We will discuss exciting possibilities but also challenges which are immanent when trying to target these stromal responses for diagnosis and therapy.