Excisional or incisional biopsies of melanoma are used to determine depth of tumor invasion and to plan subsequent treatment. Accurate determination of depth of melanoma invasion is critical for treatment decisions and prognosis. Incisional or punch biopsies can be perilous for histopathologic determination of invasion, and both over- and underestimation of invasion can occur when using incisional methods. Likewise, histologic factors can lead to over- and underestimation of invasion. Prognosis and treatment of melanoma are primarily determined by depth of tumor invasion. We discuss several scenarios that can lead to over- and underestimation of depth of invasion in incisional biopsy specimens. We therefore discourage incisional or punch biopsies of suspected melanoma and recommend that depth of invasion not be reported on these types of specimens.