We have limited understanding of the relationship between CTCs and DTCs and to study these populations in clinical samples remains technologically challenging. CTCs are heterogeneous and the majority may not ultimately form metastases. So what will a detailed analysis of their genetic makeup really tell us? In addition, collection of DTCs most commonly involves bone marrow aspirates that potentially do not capture DTCs embedded in specific bone niches. Few studies have included collection and comparison of CTCs and DTCs from the same patient. The use of in vivo model systems combined with recent technological advances in cell labelling and imaging has provided new insights into the early stages of tumour cell dissemination to the skeleton. In particular, the role of specific microenvironments or niches, as well as how DTCs residing within these niches are affected by environmental signals and therapeutic targeting, is emerging. But to what extent can this information be translated to human disease? This lecture will provide a summary of the current understanding of CTCs and DTCs in development of metastatic disease and show the latest pre-clinical data from studies of DTCs in breast/prostate cancer. The role of CTCs and DTCs will be discussed; should CTCs be used as a measure of disease burden whereas DTCs should be the main therapeutic target? How useful is CTC gene expression data for patient outcome? Do CTC have to become DTCs in order to pose a risk?