Nanoparticulate (NP) drug carrier systems are attractive vehicles for selective drug delivery to solid tumors. Ideally, NPs should evade clearance by the reticuloendothelial system while maintaining the ability to interact with tumor cells and facilitate cellular uptake. Great effort has been made to fulfill these design criteria, yielding various types of functionalized NPs. Another important consideration in NP design is the physical and functional stability during circulation, which, if ignored, can significantly undermine the promise of intelligently designed NP drug carriers. This commentary reviews several NP examples with stability issues and their consequences, ending in a discussion of experimental methods for reliable prediction of NP stability.