Metastasis is defined as a very inefficient process, since less than 0.01% of cancer cells injected into the circulation will engraft in a distant organ, where they must acquire the ability to survive and proliferate inside a “foreign” environment. In bone metastases, the interaction with the host organ is much more favoured if tumour cells gain “osteomimicry”, that is the ability to resemble a resident bone cell (i.e. the osteoblast), thus intruding in the physiology of the bone. This is accomplished by the expression of osteoblast markers (e.g. alkaline phosphatase) and the production of bone matrix proteins and paracrine factors which deregulate the physiology of bone, fuelling the so-called “vicious cycle”. The main challenge of researchers is therefore to identify the genetic profile determining the osteotropism of tumour cells, which would eventually lead to bone colonisation. This could likely provide the answer to a quite intriguing question, that is why some cancers, such as prostate and breast, have a specific predilection to metastasise to the bone. Therefore, it is important to completely address the molecular mechanisms underlying this aspect of bone oncology, identifying relevant pathways, the targeting of which could make any type of bone metastasis curable or avoidable.