Global cancer prevalence has continuously increased in the last decades despite substantial progress achieved for patient care. Cancer is no longer recognized as a singular disease but as a plurality of different ones, leading to the important choice of the drug administration route and promoting the development of novel drug-delivery systems (DDS). Due to their structural diversity, therapeutic cancer drugs present specific challenges in physicochemical properties that can adversely affect their efficacy and toxicity profile. These challenges are addressed by innovative DDS to improve bioavailability, pharmacokinetics and biodistribution profiles. Here, we define the drug delivery challenges related to oral, intravenous, subcutaneous or alternative routes of administration, and review innovative DDS, marketed or in development, that answer those challenges.