One of the most relevant problems in tumour treatment resides on the ability of the tumour to form metastasis and disseminate among the organism. The formation of metastases is a complex process, which requires the action of various effectors, not yet completely identified. The analysis of various types of tumours revealed a complex picture about the relationship between type 2 transglutaminase (TG2) expression and outcome and/or metastatic potential of the tumour itself. In some tumours, the transition to a highly invasive state is paralleled by an up-regulation of TG2 expression and/or activity while in some other a down-regulation has been reported. In addition, host tissues seem to react to tumour invasion by up-regulating TG2 expression. In order to analyse whether TG2 might be involved in the metastatic process in melanoma, we studied the metastases formation and development by means of the B16-F10 murine melanoma cell line and with TG2(-/-) mice as experimental model. Our results indicate that TG2 absence in the host is a favouring condition for the formation and development of the metastasis, while the presence of TG2 in the tumour's cell might be requested for the development of the metastasis.