The ATP-binding cassette transporters (ABC transporters) have been intensely studied over the past 50 years for their involvement in the multidrug resistance (MDR) phenotype, especially in cancer. They are frequently overexpressed in both naive and post-treatment tumors, and hinder effective chemotherapy by reducing drug accumulation in cancer cells. In the last decade however, several studies have established that ABC transporters have additional, fundamental roles in tumor biology; there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness, progression, and patient prognosis. This review highlights these studies in relation to some well-described cancer hallmarks, in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tumor development. Unraveling these new roles offers an opportunity to define new strategies and targets for therapy,which would include endogenous substrates or signaling pathways that regulate these proteins.