The accurate estimation of the time of death is a challenge in forensic medicine, as the methods routinely used to assess the post-mortem interval (PMI) are far from being precise. Over the past decades, biochemical methods have been implemented on post-mortem samples to improve the precision of PMI estimation. Studies have focussed on the biochemical profiles of closed compartment body fluids, as they are preserved longer than blood after death and are thus subject to confined post-mortem chemical changes. Cerebrospinal fluid (CSF) has been considered a suitable fluid to investigate these changes, as it is found in large amounts and is easy to sample. Moreover, the main molecules found in CSF have known reference values in living subjects, unlike most other body fluids. In this literature review, we focus on the panel of biomarkers that have been studied in CSF based on their potential of offering information on the time of death. The interest of these biomarkers in casework and the research perspectives in this field are discussed. Integrating data from different methods, including biochemistry, for better estimation of the time of death would represent a step forward in the forensic field, paving the way for an innovative approach that we suggest to call “Forensomics”.