Cerebro-spinal fluid (CSF) leak in cranial and spinal surgery seriously threatens the clinical prognosis of surgical cases exposing the patients to higher risk of infection, prolonged hospital stay, and need of reoperation. Ultimately, this cascade of events may lead to life-threatening complications, as in cases of meningitis/encephalitis, spondylodiscitis, subdural hematomas, and severe pneumocephalus. Moreover, CSF leak causes a consistent rise in healthcare-related costs which are nearly doubled in CSF leak cases after craniotomy or in spinal surgery. The risk of CSF leak tends to be higher in patients undergoing transnasal endoscopic surgery, posterior fossa craniotomies, and spinal surgery, while being considered a quite rare finding in supratentorial brain surgery. Here we analyzed the different implications of this issue focusing on the usefulness of new technologies and surgical strategies to prevent it. CSF leak rate may vary from 4% in transsphenoidal procedures to 32% in posterior fossa craniotomies. In spinal surgery, CSF leak may be a consequence of elective intradural surgery, accounting for 18% of the procedures, or being a result of incidental durotomies, ranging from 1 to 17% in different surgical series. Dural closure's reinforcement using different new dural sealants plays an important role in preventing these events. Moreover, the use of neuronavigation systems in skull base and posterior fossa surgery can help to minimize the size of approach and reduce the incidence of CSF leak. New minimally invasive spinal approaches, such as minimally invasive decompression for spinal degenerative disorders or performing selective laminotomies over laminectomies for intradural spinal pathology are very useful techniques to prevent CSF leak in this kind of surgery. In conclusion, although CSF leak remains a risky complication in neurosurgery, its prevention and treatment significantly benefited from advances in biomaterials and surgical technique.