The platinum antitumor drugs cisplatin, carboplatin and oxaliplatin are widely used components of modern cancer chemotherapy. However, their success is limited by severe adverse effects and because of the impact of intrinsic and acquired resistance mechanisms on tumor responses. Consequently, intense efforts have been made to develop new metal compounds that either display enhanced tumor specificity or are less prone to the development of resistance. Despite the synthesis of thousands of compounds during the last decades only very few novel metal drugs have successfully reached clinical development and/or approval so far. In this review we summarize the current knowledge on drug resistance mechanisms against novel metal compounds (including platinum, arsenic, ruthenium, gallium, titanium, copper, and lanthanum drugs), and address the question whether there might exist a general metal-drug resistance phenotype.