The show follows Crime Scene Investigators working for the Miami-Dade Police Department as they use physical evidence, similar to their Las Vegas counterparts, to solve grisly murders. The series mixes deduction, gritty subject matter, and character-driven drama in the same vein as the original series in the CSI franchise, except that the Miami CSIs are cops first, scientists second.

Set in present day Chicago, the ancient avenging demon Lilith, attempts to destroy a young paramedic's life while destroying anyone who interferes with her plan.