Efforts over the last few decades to extend the life expectancy of patients with chronic obstructive pulmonary disease (COPD) have faced difficulties, but our perception of the problems involved is now starting to change. Improvements in our understanding of the pathogenic and etiological mechanisms of the disease, analysis of the causes of death, and, in particular, identification of the relevant prognostic factors have resulted in firm advances that allow us to face the future with greater optimism. The aim of this review is to provide a detailed analysis of the chief prognostic factors described in the literature and to evaluate the therapeutic implications of these findings. The traditional view maintained that the accelerated decline in forced expiratory volume in 1 second over time was one of the best predictors of mortality, and this belief has for decades determined the strategies used to treat COPD. However, we now know COPD to be a multidimensional disease and are aware that some of its other manifestations have important prognostic implications. Lung hyperinflation, exercise tolerance, exacerbations, comorbidity, and systemic manifestations-in particular those related to the cardiovascular system-have all been shown in recent years to be strong predictors of mortality. The inflammatory substrate, whether local or systemic, merits special consideration because it appears to be the cause of many of these manifestations. These newly identified prognostic factors are of great interest in that it may be possible to moderate their influence, a circumstance that highlights the need to change the traditional treatment approach and devise therapeutic interventions oriented towards reversing the effects of these factors.