Some melanocytic tumors are diagnostic challenges and require ancillary tools in helping the pathologists to determine their potential of malignancy. We intend to propose a diagnostic algorithm in helping to classify challenging melanocytic tumors combining histology, immunohistochemistry, and cytogenetics. We report on 24 spitzoid and/or misdiagnosed melanocytic tumors studied with a triple p16, Ki-67, and HMB45 immunohistochemistry score, fluorescent in situ hybridization (FISH) with melanoma-dedicated and non–melanoma-dedicated probes and comparative genomic hybridization on DNA microarray (CGH array). Melanoma-dedicated FISH probe classified as favor malignant 8/8 melanomas, 1/2 atypical spitzoid tumor, and 4/14 nevi with polyploidy. Only 10 CGH array assays were contributive and concluded in complex chromosomal patterns as hallmarks of malignancy in 5 melanomas, single isolated imbalances in 3 nevi, and no chromosomal gain or loss in 2 nevi. The p16-Ki-67-HMB45 immunohistochemistry score was favor benign (ie, 0 to 3) in 13/14 nevi and in the favor benign atypical spitzoid tumor according to FISH analyses. The FISH-favor malignant atypical spitzoid tumor, 8/8 melanomas, and 1 tumor initially diagnosed as a Spitz nevus had favor malignant p16-Ki-67-HMB45 immunohistochemistry scores (ie, 4 to 9). Additional FISH analyses detected a 9p21/CDKN2A double deletion, frequently reported in melanomas but not in nevi, in the tumor initially diagnosed as a Spitz nevus with a favor malignant p16-Ki-67-HMB45 score. To conclude, in our opinion, histology and p16-Ki-67-HMB45 immunohistochemistry could consist in first-line tools to diagnose a difficult melanocytic tumor, followed by cytogenetics analyses in cases of discrepancies between histology and immunohistochemistry.