An appreciation of the histopathogenesis of skin cancer is essential to understand the rising incidence of skin cancer, the malignant behavior of aggressive tumors, the potential mechanisms for treatment targeting specific levels of carcinogenesis, and future developments in prevention. The lifetime risk of skin cancer in the United States has risen to one in six individuals. 26 Basal cell carcinoma (BCC) accounts for 75% of nonmelanoma skin cancers (NMSC) and squamous cell carcinoma (SCC) accounts for 20% of NMSC. 26 Cutaneous malignant melanoma (MM) is increasing in incidence and is responsible for 75% of all skin cancer–related deaths. The lifetime risk of melanoma in the United States has increased from 1 in 1500 in 1935 to 1 in 75 in 2000. 26 Sebaceous cell carcinoma, a life-threatening and poorly understood tumor, accounts for 1% to 5.5% of eyelid malignancies in the United States. 19 Less commonly encountered malignant tumors of the eyelid include T-cell lymphoma, Merkel cell carcinoma, Kaposi's sarcoma, and eccrine carcinoma. Pre-existing lesions, heritable and sporadic genetic mutations, environmental factors, and immunologic factors contribute to carcinogenesis. Each cutaneous neoplasm has one or several pathways of progression from normal tissue to dysplasia to malignancy. BCC, SCC, MM, and Merkel cell carcinoma (MCC) share ultraviolet (UV) radiation as one contributing factor, although SCC is less directly related to UV radiation. 65 SCC and MM, more often than other cutaneous malignancies, arise in pre-existing lesions. BCC is less inclined to metastasize and is modulated by local factors such as epidermal growth factors, cytokines, and stromal moderators of cell migration and proliferation. 65 Some cutaneous eyelid tumors may occur in genetic syndromes that predispose to cutaneous malignancy such as nevoid basal cell carcinoma syndrome (NBCCS), xeroderma pigmentosa (XP), and familial atypical multiple mole-melanoma syndrome (FAMMM). Age-related changes in cellular immunity, pharmacologic immunosuppression, and other specific and nonspecific host and tumor factors may allow tumor escape from immune surveillance. Three distinct stages of carcinogenesis—initiation, promotion and progression—are recognized but may not apply to all tumor types. 9 Initiation occurs with a gene mutation that is heritable or sporadic and permanent. Although the cell may remain dormant, under certain circumstances, this cell might proliferate if strategic growth advantage is transferred to this cell and its progeny. Additional mutational events or environmental factors may lead to selective proliferation of the mutated cell line. Promotion stage occurs with activation of a growth receptors or inhibition of regulation. 9 Further mutations produce genome instability and a malignant phenotype, which, in the rapidly proliferating cells, constitutes the progression stage. Invasion and metastasis may occur as autonomous and aggressive tumor behavior is manifested. 9 Thus, acquired or inherited genetic damage and environmental events lead to progression along the clinical spectrum of dysplasia, carcinoma in situ, and invasive disease. The goal of this article is to provide highlights of research on pathogenesis of malignant skin tumors affecting the eyelids. Research that defines biochemical, immunologic, and genetic regulation of the pathologic mechanisms initiating, promoting, and sustaining neoplasms will eventually allow specific therapy directed at various levels of carcinogenesis.