Multidrug resistance in bacteria is a major threat to global health and the effective prevention and treatment of infections. The urgent need for novel antimicrobial agents, together with the increasing challenges in discovering and developing effective antibiotics, has inspired new approaches and strategies to circumvent antibiotic resistance. Despite this effort, the difficulty in cell-penetration and delivery of antibiotics into bacterial cells remains the bottleneck for both traditional and non-traditional antibacterial agents to realize their full potential. Recently, cell-penetrating peptides (CPPs) have attracted considerable attention as low-toxicity carriers, promising the improvement of the low biological activity of traditional antimicrobial agents. CPPs are now extensively used to deliver various antibiotics, including recently developed agents, such as antisense oligonucleotides (ASOs). The conjugation of CPPs to antimicrobial peptides (AMPs) can also greatly enhance antibacterial activity and may present an effective approach for developing novel antimicrobial agents. This review discusses the characteristics, designing strategies, and recent progress in the development and application of antimicrobial CPPs as potent antibacterial agents against multidrug-resistant bacteria.