Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, and one of the main pathogens responsible for otitis media infections in children. Amoxicillin (AMX) is a broad-spectrum β-lactam antibiotic, used frequently for the treatment of bacterial respiratory tract infections. Here, we discuss the pneumococcal response to AMX, including the mode of action of AMX, the effects on autolysin regulation, and the evolution of resistance through natural transformation. We discuss current knowledge gaps in the synthesis and translocation of peptidoglycan and teichoic acids, major constituents of the pneumococcal cell wall and critical to AMX activity. Furthermore, an outlook of AMX resistance research is presented, including the development of natural competence inhibitors to block evolution via horizontal gene transfer, and the use of high-throughput essentiality screens for the discovery of novel cotherapeutics.