Basal cell carcinoma (BCC) is one of the most common skin neoplasms in humans, accounting for almost 80% of all non-melanoma skin cancers worldwide. The nodular and infiltrative-morpheaform are the most common BCC types in the head and neck region and together with the micronodular subtypes are the most aggressive tumors, because of their tendency to infiltrate the deep subcutis, muscles and even bones. To explain the local aggressive behavior and their metastatic potential, many studies have been performed to identify the molecular determinants implicated in BCC tumor progression. For this reason, we investigated the immunohistochemical expression of CXCR4, MMP-13 and β-catenin expression in six metatypical, eight infiltrative-morpheaform, six micronodular and five superficial facial BCCs. For all three markers, the tumor reactivity varied with the histological type. The highest reactivity was observed in metatypical subtype, especially at the level of areas with squamous cells differentiation. The lowest reactivity was recorded in micronodular and superficial BCC subtypes. Regardless histological subtype, the tumor reactivity was higher at the advancing edge and additional a strong stromal reaction was noticed for all investigated markers peculiar in fibroblasts, inflammatory cells and endothelial cells. All these data proved the utility of CXCR4, MMP-13 and β-catenin immunohistochemical investigation in BCCs both for identification of high-aggressive tumors and to develop novel more efficient therapeutic strategy for these patients by targeting these biomarkers.