Phage display has been used as a powerful tool in the discovery and characterization of ligand-receptor complexes that can be utilized for therapeutic applications as well as to elucidate disease mechanisms. While the basic properties of phage itself have been well described, the behavior of phage in an in vivo setting is not as well understood due to the complexity of the system. Here, we take a dual approach in describing the biophysical mechanisms and properties that contribute to the efficacy of in vivo phage targeting. We begin by considering the interaction between phage and target by applying a kinetic model of ligand-receptor complexation and internalization. The multivalent display of peptides on the pIII capsid of phage is also discussed as an augmenting factor in the binding affinity of phage-displayed peptides to cellular targets accessible in a microenvironment of interest. Lastly, we examine the physical properties of the total phage particle that facilitate improved delivery and targeting in vivo compared to free peptides.