Melanoma is a heterogeneous tumour, comprising of different cell populations that vary in their potential for growth and invasion, and sensitivity to therapy. Mutually-exclusive expression of key transcription factors MITF and BRN2 has been identified in sub-populations in melanoma patient tumours. While others found that BRN2 could repress MITF expression, we established that MITF controls BRN2 protein levels by modulating expression of a microRNA, highlighting a complex feedback loop controlling the levels of these key transcription factors. We therefore investigated the effects of depletion of MITF and BRN2 levels within the cellular population in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumour forming ability and metastatic capability in vivo. In contrast, BRN2 depletion led to a cell population with intact proliferation and invasion in vitro. However, growth following metastatic dissemination in an in vivo mouse xenograft model was significantly reduced upon BRN2 depletion. These results suggest that the proliferative population within melanoma tumours expresses MITF while the ability to extravasate from the circulation and subsequently grow requires expression of both BRN2 and MITF in the population. This may indicate heterogeneous cellular co-operation in the metastasis of melanoma. The molecular mechanisms behind this finding are currently being dissected, and will be discussed.