The biopharmaceutical industry is experiencing renewed interest in the discovery and development of peptide therapeutics, enabled in part by advances in synthetic processes, phage display technologies and combinatorial libraries that have permitted the rapid design, identification and evaluation of potential new peptide actives. With more than 100 peptide drugs already on the market as of 2018, garnering collective sales in excess of $20 billion, the promise of peptide medicines is a compelling one. Yet broad realization of peptide drugs remains elusive: limitations in biological delivery, including short half-life, rapid metabolism, proteolytic cleavage, poor permeation across biological membranes and a propensity for chemical and physical degradation, present significant challenges to peptide drug development. This chapter addresses key stability and pharmacokinetic considerations for the development of peptide drugs, identifies approaches and methodologies for their assessments in preclinical research and development and discusses current and emerging chemistry strategies to address such liabilities through predictive molecular design.