Cardiac hypertrophy, interstitial fibrosis, and cardiac dysfunction ultimately lead to cardiac failure. Cardiac failure is one of the major causes of heart disease and death in our society. The molecular causes of heart diseases, like many other diseases, remain largely unknown. Recently, large-scale proteomics studies have been undertaken to better understand the underlying mechanisms of molecular causes of heart disease. Many protein alterations have already been identified in the human diseased myocardium. Further experiments on these proteins are ongoing to know their suitability for drug targets, therapeutic proteins, or disease biomarkers. This review deals with a proteomics perspective on human heart failure, and is divided into two parts. The first part provides a glimpse on proteomics technologies used for identification and quantification of proteins related to heart disease. The second part is the main focus of this review and deals with evolving biomarkers and clinical diagnostics, potential future drugs, clinical approaches in managing heart failure, and clinical shortcomings, which are discussed to some detail from the viewpoint of a medical doctor and proteomics scientists.