Many signals have risen and fallen in the tide of investigation into mechanisms 
of myocardial hypertrophy and heart failure (HF). In our opinion, the 
multifunctional Ca and calmodulin-dependent protein kinase II (CaMKII) has 
emerged as a molecule to watch, in part because a solid body of accumulated data 
essentially satisfy Koch's postulates, showing that the CaMKII pathway is a core 
mechanism for promoting myocardial hypertrophy and heart failure. Multiple 
groups have now confirmed the following: (1) that CaMKII activity is increased 
in hypertrophied and failing myocardium from animal models and patients; (2) 
CaMKII overexpression causes myocardial hypertrophy and HF and (3) CaMKII 
inhibition (by drugs, inhibitory peptides and gene deletion) improves myocardial 
hypertrophy and HF. Patients with myocardial disease die in equal proportion 
from HF and arrhythmias, and a major therapeutic obstacle is that drugs designed 
to enhance myocardial contraction promote arrhythmias. In contrast, inhibiting 
the CaMKII pathway appears to reduce arrhythmias and improve myocardial 
responses to pathological stimuli. This brief paper will introduce the molecular 
physiology of CaMKII and discuss the impact of CaMKII on ion channels, Ca 
handling proteins and transcription in myocardium. This article is part of a 
special issue entitled "Key Signaling Molecules in Hypertrophy and Heart 
Failure".