Failed back surgery syndrome (FBSS) is a severe, long lasting and very common complication of lumbosacral spine surgery. FBSS can result from a variety of factors, such as an incorrect level of surgery, inadequate surgical decompression, recurrent disc herniation and epidural nerve fibrosis. The primary objective of this study was to present the recent data from animal and clinical studies regarding a variety of biological, pharmacological, and different synthetic materials used to prevent scar formation after spine surgery. There are a substantial number of substances that are topically used on the dura mater to prevent epidural fibrosis; however, we have primarily selected the substances that are used most often, such as hyaluronic acid (HA) and its derivatives, mitomycin C (MMC), 5-fluorouracil (5-FU), tacrolimus, melatonin (MLT), and nonsteroidal anti-inflammatory drugs (NSAIDs). Other biological and synthetic materials are also presented, which are used locally in the dura mater but act as mechanical barriers, such as Adcon-L, amniotic membrane (AM), carboxymethylcellulose and polyethylene oxide (CMC/PEO), polytetrafluoroethylene (PTFE), chitosan, collagen dural matrix, polyethylene glycol hydrogel, and fibrin sealant-based medicated adhesion barrier. As indicated in this review paper, the results regarding the use of these substances and barriers in animal models and humans are different; their effects have not always been successful, and they may have even caused adverse effects. However, it is necessary to identify adequate chemical, biological, and synthetic substances that are more successful in the prevention of epidural fibrosis, which is considered one of the main causes of FBSS.