Purpose: Lichen sclerosus (LS) is an inflammatory skin disorder affecting anogenital areas in males and females and has been associated with squamous cell carcinoma (SCC); however there is a lack of data on the role of biomarkers for the prediction of LS progression to SCC. This review focuses on early protein markers of SCC and their expression in LS to improve the mechanistic and diagnostic understanding of LS. Material and Methods: We performed an extensive PubMed and MEDLINE search of protein markers found in early stages of vulvar and penile SCC and their prevalence in associated LS lesions. Results: In recent years, several markers have been implied as precursor markers for malignant transformation of LS into SCC; these include p53, Ki-67, gamma-H2AX, MCM3, and cyclin D1. These proteins show upregulation in both LS of vulva/penis and SCC and various levels of evidence have been reported regarding an association between LS and SCC. p16 is overexpressed in penile and vulvar SCC associated with HPV infection and conflicting reports exist about its expression in LS. Angiogenesis markers VEGF, COX-2 and MVD are reported to be expressed at higher levels in vulvar LS and SCC indicating a possible similar association in penile LS. Conclusions: Only a minority of LS cases are associated with SCC. However, therapeutic implications of the diagnosis of SCC are severe. Clinically, we lack understanding as to separate indolent LS cases from those in danger of progression to SCC. Several protein markers show promise in further delineating the pathobiology of LS and the potential malignant transformation into SCC.