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Immunohistochemistry (IHC) is now one of the main adjunctive methods to conventionally stained sections in histopathology. This is mainly related to the fact that it is a relatively simple, fast, and inexpensive method. Due to technical advances, there has been a significant increase in the number of diagnostic immunohistochemical markers available for pathologists and dermatopathologists in recent years. The sensitivity and specificity of certain antibodies, their staining pattern (nuclear, cytoplasmic, or membranous), and background artifact must be considered in their interpretation. In addition, evaluation must be done in relation to internal control. IHC, however, is only a tool to be used appropriately in the context of clinical and histopathologic correlation; unreasonable use can be misleading and financially cost ineffective. In this review, we highlight the main available immunohistochemical markers that have been used for diagnosis of neoplasms with eccrine and apocrine differentiation. Although the diagnosis of neoplasms showing secretory apocrine differentiation is straightforward, specific markers for histopathologic differential diagnosis between eccrine and apocrine ductal neoplasms are still missing. In any case, numerous markers are now available to assist the dermatopathologist in the diagnosis of these neoplasms, supporting true ductal differentiation and helping in the distinction between primary and metastatic adenocarcinomas in the skin.