Nanotherapeutics is a burgeoning field in cancer therapy that may address some of the issues associated with systemically administered chemotherapeutics, including a non-specific mechanism of action and a poor biodistribution profile, which results in dose-limiting toxicities. However, many of the nanoparticle (NP) formulations approved for clinical use in solid tumor therapy provide only modest improvements in patient survival. This is in part due to rapid clearance from the circulation, inability to efficiently target tumor cell drug uptake, and NP tumor penetration barriers, including a dense and complex extracellular matrix (ECM) and an elevated interstitial fluid pressure. These barriers hinder the penetration of drugs and NPs into and within tumors limiting therapeutic efficacy. Fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed at low levels in normal tissues but highly expressed in over 20 solid cancer types. Thus, Fn14 has the potential to be an ideal candidate for the development of targeted therapy and its down-regulation may contribute to positive disease outcomes. However, while targeting therapeutics to specific disease components may decrease some of the limitations mentioned, in order to fully capitalize on the potential benefits of targeting, low levels of non-specific adhesivity and off-target binding must be maintained in setting off an effective level of target-specific binding. My thesis project tests the hypothesis that biodegradable, polyethylene glycol (PEG)- and anti-Fn14 antibody-coated, drug-loaded NPs will exhibit high efficacy against Fn14-positive tumors due to their ability to penetrate tissue and effectively target Fn14-positive cancer cells. We tested this hypothesis in the following Specific Aims: 1) Determine the thresholds for NP size and PEG density for effective tumor penetration and examine the potential penetrative capacity of FDA-approved NPs used for breast cancer patients, 2) Determine if Fn14-targeted and/or non-targeted tissue-penetrating, paclitaxel (PTX)-loaded biodegradable NPs are more effective than the FDA-approved NP formulation Abraxane in reducing primary and metastatic breast cancer growth, and 3) Evaluate the potential use of our biodegradable NP formulation against glioblastoma (GBM), the most common and deadly form of adult brain cancer, by examining NP dispersion, cellular uptake, and tumor retention in a murine model of GBM. These findings will generate new knowledge related to the value of tumor-specific targeting for NP therapeutics.