Oral antibiotics are integral for treating inflammatory acne based on what is understood about the pathogenesis as well as the role of Cutibacterium acnes. However, rising concerns of antibiotic resistance and the perception of "antibiotic phobia" create potential limitations on their integration in an acne treatment regimen. When prescribing oral antibiotics, dermatologists need to consider dosage, duration, and frequency, and to avoid their use as monotherapy. These considerations are important, along with the use of newer strategies and compounds, to reduce adverse-event profiles, antibiotic resistance, and to optimize outcomes. Aside from concomitant medications, allergies, and disease severity, costs and patient demographics can influence variability in prescribing plans. There are multiple published guidelines and consensus statements for the USA and Europe to promote safe antibiotic use by dermatologists. However, there is a lack of head-to-head studies and evidence for comparative superiority of any individual antibiotic, as well as any evidence to support the use of agents other than tetracyclines. Although oral antibiotics are one of the main options for moderate to severe acne, non-antibiotic therapy such as isotretinoin and hormonal therapies should be considered. As newer therapies and more outcomes data emerge, so will improved management of antibiotic therapy to foster patient safety.