Erythrodermic cutaneous T-cell lymphoma (E-CTCL) is the cause of less than 5% of all cases of generalized erythroderma. A methodical evaluation of skin, blood, and lymph node samples using standard histology, immunohistochemistry (IHC), flow cytometry (FC), and molecular analysis for evidence of a dominant T-cell clone has been recommended in a recently published diagnostic algorithm. In this commentary, the author discusses available information regarding the role of these diagnostic methods for the diagnosis of E-CTCL with emphasis on personal observations regarding skin IHC and polymerase chain reaction (PCR)-based molecular studies as adjunct diagnostic studies on a series of 55 patients with erythrodermic mycosis fungoides and 50 patients with Sézary syndrome compared to 50 patients with extensive benign inflammatory skin disease. The conclusions are (1) IHC of the skin does not reliably differentiate E-CTCL from benign simulants, (2) presence of phenotypically abnormal T cells in the blood or expanded subsets of CD4+CD7- or CD4+CD26- cells by FC is particularly helpful as a diagnostic study, (3) the presence of an identical T-cell clone in the skin and blood also is a specific diagnostic criterion for E-CTCL, but exceptions may occur, and (4) the PCRgamma-denaturing gradient gel electrophoresis technique appears to be more reliable than PCRgamma-single-stranded conformational polymorphism for diagnostic purposes.