Clear aligner therapy (CAT) has gained widespread adoption for managing malocclusions, primarily due to its aesthetic advantages, improved access for hygiene, and enhanced patient comfort relative to fixed appliances (FAs). However, CAT introduces a distinct intraoral environment that can influence microbial composition, biofilm development, and host immune responses. This chapter explores the effects of clear aligners on dental and periodontal health, oral microbial communities, and immunological parameters. Evidence indicates that CAT may facilitate plaque and biofilm accumulation, particularly on composite attachments, thereby increasing the risk of white spot lesions (WSLs), gingivitis, and dental caries. Despite these risks, aligners are generally associated with lower levels of pathogenic bacteria compared to FAs. Microbiome analyses of subgingival plaque and saliva reveal shifts in bacterial genera and phyla, although these changes are frequently non-pathogenic. CAT has demonstrated minimal negative effects on clinical periodontal indices, including the plaque index and gingival bleeding index, particularly when effective oral hygiene is maintained. Furthermore, aligners may reduce sustained immune activation by limiting plaque retention and aseptic inflammation, potentially decreasing the expression of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Although hypersensitivity reactions to aligner materials are infrequent, they warrant consideration. Overall, CAT appears to support periodontal health and promote a more stable oral microbial environment compared to FAs. Continued patient adherence to hygiene protocols and further long-term studies are necessary to fully evaluate systemic implications and optimize clinical outcomes.