One of the major challenges in the field of nucleic acid delivery is the design of delivery vehicles with attributes that render them safe as well as efficient in transfection. To this end, polycationic vectors have been intensely investigated with native polyethylenimines (PEIs) being the gold standard. PEIs are highly efficient transfectants, but depending on their architecture and size they induce cytotoxicity through different modes of cell death pathways. Here, we briefly review dynamic and integrated cell death processes and pathways, and discuss considerations in cell death assay design and their interpretation in relation to PEIs and PEI-based engineered vectors, which are also translatable for the design and studying the safety of other transfectants.