In recent years, we have seen a rapid transformation in the standard of care for non-small-cell lung cancer. Particularly in the last decade, immunotherapy has become common at almost every stage of lung cancer. Unfortunately, immunotherapies are not effective for every patient. There are many postulations about the ineffectiveness of immunotherapies, e.g., some non-targetable and/or co-occurring mutations might cause resistance to immunotherapy, while some actionable mutations might lead to a better response to immunotherapy. Hence, in addition to traditional predictive biomarkers, it is now recommended to investigate the presence of both targetable and non-targetable mutations by detailed genomic analysis to optimize the decision on mono-immunotherapy. There is ongoing research about the biomarkers that could be strong predictors of the outcomes with first-line and subsequent mono immunotherapy. In addition, the impact of clinical negative predictive biomarkers is debatable. The present work aims to discuss these controversies and challenges.