In this article we present the path that led to current concepts regarding antimicrobial treatment of endocarditis caused by viridans streptococci highly susceptible to penicillin. Early treatment trials indicate that some patients with subacute endocarditis can be cured with shorter treatment duration than currently advised by international guidelines. Also, high-dose antibiotics, as recommended today, have a predominantly pharmacokinetic and pharmacodynamic rationale that is based mostly on experimental animal studies. Shortening antimicrobial treatment in select patients with endocarditis would be of great benefit. As yet there are no predictors of cure that can be used to individualize treatment duration in patients with bacterial endocarditis.