Major advances in carrier-mediated agents, including nanoparticle, conjugates and antibody-drug conjugates, have created revolutionary drug delivery systems in cancer over the past two decades. While these agents provide several advantages, such as greater duration of exposure and solubility, compared with their small-molecule counterparts, there is substantial variability in delivery of these agents to tissues and especially tumors. This review provides an overview of tumor microenvironment factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents observed in preclinical models and patients.