Malassezia spp. are lipophilic yeasts not only present in the normal skin microflora, but also responsible of skin-related diseases (pityriasis versicolor, seborrheic/atopic dermatitis and dandruff) as well as systemic fungal infections in humans and animals. Their treatment and eradication are mainly based on old azole drugs, which are characterized by poor compliance, unpredictable clinical efficacy, emerging resistance and several side effects. These drawbacks have prompted the research toward novel synthetic and natural derivatives/ nanomaterials targeting other pivotal enzymes/pathways such as carbonic anhydrase (MgCA) and lipases, alone or in combination, in order to improve the eradication rate of this fungus. This review accomplished an update on this important topic dealing with the latest discoveries of synthetic scaffolds and natural products for the treatment of Malasseziaspp.-related diseases, thus suggesting new opportunities to design innovative and alternative anti-dandruff drugs.