In this review we will report about particular aspects of non-viral oligonucleotide delivery in vitro, pinpointing the current limitations, and provide quantitative means for determining where the bottlenecks of such strategies at present are. The focus of this article is recent progress in the field of peptide-mediated cellular delivery of siRNA and steric block oligonucleotides in cell tissue culture as a starting point for further developments illustrated by own experimental data. Our intention is not to provide the reader with easy solutions on how to solve the existing problems encountered with such approaches but give some hints where to start optimizing a particular approach.