It is well documented that signal peptides (SPs) play an important role in the cellular processing and secretion of peptides and proteins. During translation-associated translocation into the endoplasmic reticulum, SP are cleaved from the nascent proprotein and, with a few notable exceptions, it has been generally assumed that the SP is then destroyed or recycled. Thus, like a bus ticket, the SP is considered to have served its purpose in the endoplasmic reticulum, allowing protein transport and secretion to proceed and is of no real further use. In this short review, we present evidence that this view may require reassessing. Indeed, we tentatively suggest that SP may be an unaccounted portion of protein translation that makes its way into the human circulation and may have abilities besides their known role in cellular protein production.