Metastatic lesions are the leading cause of death among cancer patients. These lesions usually originate from clonal proliferation of single tumor cells dispersed from the primary tumor into the circulation which finally arrest in the capillary bed of distant organs. The microenvironment within the circulation of potential metastatic target organs provides a variety of pro- and anti- metastatic stimuli regulating the onset of organ colonisation by metastatic tumor cells. Mechanical shear stress, anoikis and cell mediated cytotoxicity within the microcirculation probably clear most circulating tumor cells. Adhesion, and eventually extravasation, are essential initial interactions of circulating tumor cells with distant organs and can provide escape from the cytotoxic environment within the circulation. Adhesion to the capillary wall is mostly controlled by the organ-specific availability of adhesion molecules on tumor cells, the endothelium, and the composition of the underlying extracellular matrix. The availability of pro-adhesive and pro-migratory paracrine signals provided by the organ specific microenvironment can further initiate the onset of metastatic organ colonisation. Tumor cell and microenvironment factors regulating survival within the microcirculation, adhesion and extravasation of tumor cells are highlighted in the review.