This article focuses on the promising roles of cell penetrating peptides (CPPs) in local drug delivery. Cell penetrating peptides have vast applications in drug delivery, however the mechanisms of cellular uptake is still a controversy topic. The challenges in determining the exact cellular uptake hinders further understanding of the fate of these peptides. These challenges include the lack of a reproducible way to ascertain the mechanism of entry. In addition, the in-vitro work on cell-lines did not end in definite answer to the cellular uptake mechanism. Indeed, the unreliability of such work seems logical due to different reasons, including the cell line-dependent uptake and the cell membrane heterogeneity of different types of cells. Although several CPPs reached the clinical trials, no one could reach the market, yet. Re-evaluation era should be started through moving forward for more researches on the roles of CPPs in Local delivery to homogeneous cell population of specific tissue or organ of the body. While this article demonstrates an example on variability in cellular uptake in different cell lines, it encourages more sophisticated work to be conducted on CPPs for ocular, nasal, transdermal, buccal and even inner ear delivery.