With the rapid expansion of the ethanol industry, the feeding landscape familiar to the feedlot industry is changing. While concerns regarding rising corn prices persist, many within the industry are looking at distiller’s grains, a by-product of ethanol production, to serve as a feed substitute. The question remains as to what extent these two feed sources are substitutable. The purpose of this study is to identify the economically optimal inclusion rate of distiller’s grains in beef feedlot rations, considering an array of often omitted factors. Most currently prevailing recommendation rates are strictly biologically based and frequently reference only one feeding trial. Unique economic factors considered in this research include the impact of by-product inclusion rates on animal performance (utilizing recently conducted meta-analysis from 17 relevant feeding trials), enhanced likelihood of death loss from heightened sulfur content, and manure disposal costs. Results indicate that excluding these factors can significantly impact optimal inclusion levels and that reliance on a single or few feeding trials may greatly bias results.