Bacterial infection remains a major complication answering for the failures of various implantable medical devices. Tremendous extraordinary advances have been published in the design and synthesis of antimicrobial materials addressing this issue; however, the clinical translation has largely been blocked due to the challenge of balancing the efficacy and safety of these materials. Here, calcium's biochemical features, natural roles in pathogens and the immune systems, and advanced uses in infection medications are illuminated, showing calcium is a promising target for developing implantable devices with less infection tendency. The paper gives a historical overview of biomedical uses of calcium and summarizes calcium's merits in coordination, hydration, ionization, and stereochemistry for acting as a structural former or trigger in biological systems. It focuses on the involvement of calcium in pathogens' integrity, motility, and metabolism maintenance, outlining the potential antimicrobial targets for calcium. It addresses calcium's uses in the immune systems that the authors can learn from for antimicrobial synthesis. Additionally, the advances in calcium's uses in infection medications are highlighted to sketch the future directions for developing implantable antimicrobial materials. In conclusion, calcium is at the nexus of antimicrobial defense, and future works on taking advantage of calcium in antimicrobial developments are promising in clinical translation.