Definitions for susceptibility or resistance of Streptococcus pneumoniae to penicillin were not developed until penicillin-resistant pneumococci appeared in South Africa in the late 1970s. The definition that was accepted (which still remains in use) and later definitions of resistance to most other β-lactam antibiotics were derived from laboratory and clinical data relating to the treatment of meningitis, not otitis media, sinusitis, or pneumonia. An understanding of the origin of these definitions helps to resolve the apparent paradox that infections of the respiratory tract due to seemingly β-lactam–resistant pneumococci may still respond well to standard doses of these drugs. A recently sanctioned change in the definition of susceptibility to amoxicillin is helpful in eliminating the paradox for this drug, but it may create further confusion by implying that, on a microgram basis, amoxicillin is substantially more effective than penicillin or third-generation cephalosporins. This article examines definitions of susceptibility and resistance of pneumococci, highlighting areas that have led to confusion and proposing a new way of understanding them.