Unlike bacterial protein synthesis, eukaryotic protein synthesis has several mechanisms to initiate translation including cap-dependent initiation, re-initiation and internal initiation. While there is extensive biochemical characterization of the multiple steps in cap-dependent initiation, most of the information on the other two mechanisms is derived from studies on the nucleic acid sequences that influence their efficiency. However, even in the best of circumstances, both re-initiation and internal initiation are only 25% as efficient as cap-dependent initiation and more commonly, are only 1-10% as efficient. This general lack of efficiency leaves open possibilities for mis-interpretation/artifacts in vivo (cryptic promoters, alternate splicing) or in vitro (nuclease degradation). Two examples are cited from the author's laboratory as background for the development of a general set of guidelines to minimize errors and validate authenticity for internal initiation.