Oral Bioavailability (OB) is defined as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action” by FDA. For the pharmaceutical industries, high OB is often the major consideration in the development of bioactive molecules as therapeutic agents. Meanwhile, for the drugs administrated by the oral route, OB is indisputably one of the most important pharmacokinetic parameters owing to its indicator role for the efficiency of the drug delivery to the systemic circulation. Unfortunately, OB measured in vivo is labor intensive, time-consuming and prone to error. Therefore, in silico methods that can predict OB reliably and quickly are good alternatives. In this comment, an OB issue encountered during the course of prediction is described, including possible challenges and strategies.