Despite the great importance placed upon the operation of abduction as an inferential process, few studies have been devoted specifically to the process of guessing as a piece of the abduction puzzle. This is surprising since Charles Peirce indicated that guessing is a fundamental part of the abductive process. Most literature concerning Peirce's conception of abduction mentions guessing only in passing; what guessing actually is, especially with regard to the abductive process, is left vague at best, and this leaves a blind spot in the literature so that the broader conception of abduction remains unclear. In response to this, I explain the role of guessing in Peirce's concept of abduction, placing the operation of guessing within the wider scope of the process of inquiry. I consider the guessing process as a deliberate and creative part of abduction, as well as alternative claims that have led to neglect of guessing as a creative operation. This analysis includes consideration of ethical, esthetic, and economic aspects of the guessing process as described by Peirce. As a specific example to elucidate how guessing functions within a particular scientific domain, I utilize the index case of AIDS. My argument sets the stage for further work to be done concerning the function of guessing as it pertains to scientific inquiry more generally.