Therapeutic peptides (TPs) are a class of peptide-based agents capable of eliciting a therapeutic response by modulation of targets within or on the surface of cells. TPs are advantageous because they are amenable to rational design, they have high specificity for their targets and can be made to target almost any protein of interest, including proteins for which we have no small-molecule drugs. Owing to this versatility, TPs have a great potential for cancer therapy in an age of personalized medicine, in which we need novel drugs to target the many novel pathways being discovered as tumor drivers. However, in order to utilize TPs as drugs, many obstacles must be overcome. TPs have short half-lives in systemic circulation, are easily degraded by proteases in plasma and target cells, are often cleared by the reticuloendothelial system and can be immunogenic. This article will discuss ways of overcoming many of these hurdles by utilizing macromolecular peptide delivery systems and tumor-targeting agents.