The recent increase in the number of missing persons and unidentified dead in the U.S., which has resulted in the consequence of an increase in the total count of cold cases, has triggered multiple requests from medical examiner’s offices and law enforcement agencies to re-evaluate original biological profiles derived from these unsolved cases. General misconception that a positive DNA match can always be provided in conjunction with questionable, mostly outdated methodology used for profiling and incorrect understanding of geographic origins of deceased individuals has led to many erroneous assessments of biological parameters. This chapter illustrates how these cases can be solved by a complex multifactorial analysis relying on more than a single strategy. In the present study, a geometric morphometric landmark-based approach was combined with an analysis of strontium, oxygen and hydrogen isotopes and applied to North Carolina cold cases. Although official reports indicate that the geographic origin of Hispanics in North Carolina is approximately 61 % Mexican, the region of provenance for deceased immigrants found in these states is less straightforward. The analyzed indicators suggest that the re-examined cold cases are morphologically closer to samples from Panama and Guatemala rather than to Mexican individuals. The combined approach also shows that although the point of entry for the undocumented immigrants is likely the US-Mexico border other regions of origin such as South America (Peru, Chile), Honduras and El Salvador should be considered.