Sudden cardiac death (SCD) is the most common cause of death and often occurs in low-risk patients. Present prevention strategies, mainly confined to high-risk subjects (proposed implantable cardioverter defibrillators recipients), have a limited effect on SCD burden in the general population. A relatively unexplored strategy for extending SCD prevention could imply targeting the early (upstream) processes of the complex cascade leading to SCD by non-antiarrhythmic drugs (i.e., beta-blockers, aldosterone antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor-blocker agents, statins and omega-3 fatty acids). In this innovative pharmacological perspective, agents with upstream effects may also be used in high-risk patients in association with a strictly downstream intervention, such as the implantable cardioverter defibrillator, in an attempt to obtain an additive/synergetic effect.