The ability to obtain the proper clinical diagnosis in cases of suspected intraocular tumors has greatly advanced during the past 50 years. The clinical characteristics of most intraocular tumors (size, shape, color, and texture) are detectable by skilled ophthalmoscopic examination and, with the use of adjunctive techniques (mainly ultrasonography), the proper diagnosis can be reached without invasive procedures. Notwithstanding, some intraocular tumors need to be biopsied to obtain a reliable diagnosis. In the cytogenetic era, intraocular tumor management is changing, and tumor-sampling procedures are becoming the main prognostic (and theoretically also diagnostic) tools for uveal melanoma. In spite of the widespread use of biopsies in general surgical practice, in ophthalmic oncology, indications and contraindications for biopsy continue to be under debate. The purpose of this paper is to critically evaluate the role of uveal melanoma biopsy in current clinical practice.