CODIS generates investigative leads in cases where biological evidence is recovered from the crime scene. Matches made among profiles in the Forensic Index can link crime scenes together, possibly identifying serial offenders. Based upon a match, police from multiple jurisdictions can coordinate their respective investigations and share the leads they developed independently. Matches made between the Forensic and Offender Indexes provide investigators with the identity of suspected perpetrators. Since names and other personally identifiable information are not stored at NDIS, qualified DNA analysts in the laboratories sharing matching profiles contact each other to confirm the candidate match.

Deoxyribonucleic acid (DNA) analysis can occur in body fluid stains and other biological tissues recovered from items of evidence. The DNA testing results obtained from evidence samples are compared to DNA from reference samples collected from known individuals. Such analyses may be able to associate victims and suspects with each other, with evidence items, or with a crime scene. The FBI can conduct nuclear, Y-chromosome, and/or mitochondrial DNA testing on evidence samples as appropriate.

These known DNA profiles are then searched against unknown forensic profiles from crime scenes across the country. If a match is identified, the casework laboratory can request FDDU to confirm the offender sample DNA profile. Once the profile is confirmed, the FDDU will then release the subject's personal identifying information back to the casework laboratory. This information can then be passed on to investigators in the hopes of apprehending the perpetrator. Thanks to law enforcement agencies and their sample submissions, FDDU has uploaded over one million profiles to NDIS and has aided thousands of investigations to date.