Chronic heart failure (CHF) is of constantly growing importance regarding incidence, prevalence and social and economic burden. The classical mere hemodynamic perception of CHF pathophysiology has been expanded towards a much more complex and inclusive approach combining neuroendocrine, inflammatory, metabolic and immunological factors. With this advance, new parameters and targets have been shifted into the focus of current investigations, and new therapeutic approaches have been tested. Several recent studies have failed, however, despite intriguing pathophysiological concepts and promising pilot data. In other studies, significant benefits have been observed in certain subgroups only, suggesting a tailored approach for individual risk and co-morbidity situations. The contemporary concept of CHF treatment is designed to shield the heart from adverse (over)compensatory mechanisms particularly of neuroendocrine activation. This shield needs to be expanded on systemic effects including both immunologic and metabolic aspects within CHF pathophysiology. New and future concepts in CHF therapy may not yield a homogenous treatment option applicable for every patient, but may require a new range of diagnostic strategies to design a tailored therapy, adapted to the patient's pathophysiological fingerprint. This review will focus on recent developments and potential future candidates of pharmacological CHF therapy.