In a previous publication, we used kinetic models to simulate the physical movement ofthe transfer RNA (tRNA) in the cytoplasm of Escherichia coli and concluded that tRNA molecules are not able to approach the ribosome by random Brownian motion at a sufficient rate for protein synthesis. In this paper, we propose three mechanisms to explain tRNA pre-selection (to distinguish it from initial selection, we refer to it in this article as “pre-selection”) in prokaryotes. The first hypothesis is that the ribosome stores tRNA molecules inside its structure and aids in the pre-selection process. Because no previous reports in literature support such a pre-selection process, we believe that this hypothesis is unlikely. The second hypothesis suggests distant signaling between the ribosome and the cognate-transfer RNA (ctRNA) that allows the correct ctRNA to approach the ribosome and bind to the “A site.” Again, no experimental proofofa signaling mechanism between the ribosome and ctRNA exists when they are distant from each other, which renders this hypothesis invalid. Third, we hypothesize that the messenger RNA (mRNA) could act as a “comb” which is able to filter out the consecutive tRNAs from the cytoplasm, thus allowing the correct ctRNA to reach the “A site” in the ribosome. Although the functions of tRNAs, how they are assembled, and how they get charged by amino acids are widely studied and well understood, few articles report on the mechanism by which tRNAs are pre-selected and how they reach the site of amino-acid assembly, the ribosome. This article suggests several mechanisms to explain this pre-selection process.