Particles that have the potential to deliver imaging agents and drugs to cells and tissue now have many different shapes and sizes. This diversity in particle shape could provide new options for potential treatments of diseases because geometry affects biodistribution. However, the myriad of particle shapes now available increases the number of variables or parameters that must be taken into consideration for the drug delivery field to understand particle-cell interactions. This is especially true when the shape of a particle is a tunable parameter along with particle chemistry, charge, and hydrophobicity. Here we review the impact of shape on particle-cell interactions in vitro and the ramifications of different particle geometries on circulation, biodistribution, localization to tumors, and toxicology in rodents.