Anisotropic II-VI semiconductor nanostructures are important photoactive materials for various energy conversion and optical applications. However, aside from the many available surface chemistry studies and from their ubiquitous photodegradation under continuous illumination, the general chemical reactivity and thermal stability (phase and shape transformations) of these materials are poorly understood. Using CdSe and CdS nanorods as model systems, we have investigated the behavior of II-VI semiconductor nanorods against various conditions of extreme chemical and physical stress (acids, bases, oxidants, reductants, and heat). CdSe nanorods react rapidly with acids, becoming oxidized to Se or SeO₂. In contrast, CdSe nanorods remain mostly unreactive when treated with bases or strong oxidants, although bases do partially etch the tips of the nanorods (along their axis). Roasting (heating in air) of CdSe nanorods results in rock-salt CdO, but neither CdSe nor CdO is easily reduced by hydrogen (H₂). Another reductant, n-BuLi, reduces CdSe nanorods to metallic Cd. Variable temperature X-ray diffraction experiments show that axial annealing and selective axial melting of the nanorods precede particle coalescence. Furthermore, thermal analysis shows that the axial melting of II-VI nanorods is a ligand-dependent process. In agreement with chemical reactivity and thermal stability observations, silica-coating experiments show that the sharpest (most curved) II-VI surfaces are most active against heterogeneous nucleation of a silica shell. These results provide valuable insights into the fate and possible ways to enhance the stability and improve the use of II-VI semiconductor nanostructures in the fields of optics, magnetism, and energy conversion.