On a global scale, lung cancer is the most widespread and deadly type of cancer and the non-small cell lung cancer histological subtype, contributes to a significant proportion of this mortality. It has been recently proposed that the main drivers of cancer progression and chemoresistance are cancer stem cells which can be identified through numerous biomarkers or through the overactivation of developmental signaling pathways which are essential for embryonic development but are normally suppressed in adulthood. The primary aim of this review was to compile experimental findings about mediators of three signaling pathways, namely Sonic Hedgehog, Notch and Wingless Integrated, in the prognosis and targeting of three non-small cell lung carcinoma histological types, namely adenocarcinoma, squamous cell carcinoma and large cell neuroendocrine lung carcinoma. Some mediators of all three signaling pathways can be used as biomarkers and overactivation is associated with shorter overall and disease-free survival of patients accompanied by metastasis, epithelial-to-mesenchymal transition and the acquisition of chemoresistance and radioresistance. Additionally, using antagonists to block overexpressed pathway mediators has yielded promising results in vitro with significant apoptotic and anti-tumor activity. Finally, numerous novel mediators of the three pathways have been identified and their pharmacological targeting has resulted in promising pre-clinical findings. The first in-human clinical trials of several drugs are currently being conducted. The current review supports further exploration of the three developmental signaling pathways in the prognosis and targeted treatment of non-small cell lung carcinoma with the aim of enhancing current treatment guidelines with the implementation of targeted therapies.