Despite enormous advances in the past few years with new therapies for advanced melanoma, there remains considerable unmet clinical need for those patients who do not have BRAF mutations and/or do not respond to immunotherapy. We have focused on developing novel small molecule inhibitors of melanoma growth that could be useful in advanced disease. We have previously shown that microRNA-7, a short non-coding tumour suppressor RNA, is a potent inhibitor of melanoma cell viability and in vivo melanoma growth. We have subsequently focused on another small molecule, ciclopirox olamine (CPX), the major constituent of a widely used anti-fungal cream. Our studies show that CPX inhibits the viability of multiple human melanoma cells irrespective of their sensitivity to targeted therapies such as BRAF inhibitors (BRAFi). This is due to a reduction in signalling via several pathways, including the Wnt/b-catenin pathway. CPX is synergistic with combinations of targeted therapies (BRAFi and MEKi). Our preclinical studies demonstrate that CPX is a potent inhibitor of melanoma growth and formed the basis for a program to develop novel CPX analogues with enhanced stability and potency. One or more of these analogues may progress towards an early phase clinical trial in patients with advanced melanoma.