Recent studies have shown mutually-exclusive expression of the key transcription factors BRN2 and MITF in melanoma patient tumours. Intravital imaging has shown heterogeneous expression of BRN2 and MITF is found in xenografted tumours, whereas circulating tumour cells show only high BRN2 expression. Subsequent lung metastases revert to heterogeneous expression of BRN2 and MITF. BRN2 is known to repress MITF expression. We have recently found that MITF controls BRN2 protein levels, highlighting a novel feedback loop for the expression of these key transcription factors. This opens a new direction in understanding melanoma development, and may enable effective targeting of treatment to prevent melanoma recurrence.