Immunocytochemistry (ICC) is a widely available and extensively used ancillary method in diagnostic cytopathology with great variability in all test phases and a low level of adequate quality management. The non-standardized ICC landscape is now challenged with the introduction of the new European (EU) In Vitro Diagnostic Medical Devices Regulation (IVDR). According to this regulation, ICC on cytological slides falls under the category of Laboratory-Developed Tests (LDT), which requires rigorous standardization, validation, and thorough quality management. Complete standardization of pre-analytical and analytical steps in ICC is impossible due to the complexity of the method and the constantly evolving antibodies, detection systems, and platforms. However, similar to the approach in immunohistochemistry, improving and standardizing "best practices" in quality management will result in high-quality, correct, accurate, and reliable ICC results. In this review, the current challenges of ICC in diagnostic cytopathology will be discussed, along with practical insights into ICC standardization and validation. Control slides prepared in the same manner as the patient samples, optimized ICC protocols, and participation in external quality control for ICC are the pillars of good quality management and essential to ensure safe and reliable patient diagnostics.