Background: The most significant biomarkers that are included in the Alzheimer’s disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration. Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers’ tests. The controversies regarding the use of biomarkers in the clinical practice are related to the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes. Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context. Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work. Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes. Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological.