Protein neddylation is a ubiquitylation-like post-translational modification, catalyzed by a cascade consisting of three enzymes: NEDD8-activating enzyme E1 (NAE), an NEDD8-conjugating enzyme E2 (UBE2M or UBE2F), and NEDD8 E3 ligases. Cullin family proteins are the physiological substrates of neddylation, and Cullin neddylation activates Cullin-RING ligases (CRLs). CRLs are the largest ubiquitin E3 ligase family and mediate the ubiquitylation of ~20% cellular proteins to regulate many biological processes, including cell cycle, DNA damage response, cell growth, metabolism, survival, autophagy, migration, and immune escape. In the process of deneddylation, NEDD8 is hydrolyzed and removed from the substrate protein by specific deneddylation enzymes, and is released into cells to maintain the dynamic balance of the neddylation/deneddylation. NEDD8 and NEDD8 enzymes are overexpressed or upregulated in a variety of cancers, leading to excessive activation of CRLs and subsequent degradation of many tumor suppressor proteins, thereby promoting the growth and survival of lung cancer cells, and lung tumorigenesis. Protein neddylation has been validated to be a promising target for anti-cancer therapy. Similarly, some deneddylation enzymes are highly expressed in lung cancer and their changes are also closely related to the growth and tumorigenesis of various malignant tumors, thus is a potential target for anti-cancer therapy. In this review, we mainly focus on the role of protein neddylation/deneddylation in lung cancer, how the expression of neddylation and deneddylation pathways is changed in lung cancer cells, and how they regulate the growth and survival of lung cancer cells, as well as the lung tumor microenvironment and the related inflammatory/immune response. A better understanding of the role of key components of neddylation/deneddylation pathways in the promotion of lung cancer cell growth and tumorigenesis and establishment of lung tumor microenvironment will provide a sound rationale for targeting this pathway for effective lung cancer therapy.