Tumor necrosis factor (TNF)-alpha, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lungs. Given that there is significant literature supporting the pathobiologic role of TNF-alpha in asthma, mainly in severe refractory asthma, and COPD, TNF-alpha inhibitors (infliximab, golimumab and etanercept) are now regarded as the potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-alpha inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-alpha inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-alpha, perhaps in a more carefully selected patient group. TNF-alpha treatment should, therefore, not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-alpha inhibitors.