Lip inflammation may manifest as mainly reversible cheilitis, mainly irreversible, or cheilitis connected to dermatoses or systemic diseases. Therefore, knowing a patient’s medical history is important, especially whether their lip lesions are temporary, recurrent, or persistent. Sometimes temporary contributing factors, such as climate and weather conditions, can be identified and avoided—exposure to extreme weather conditions (e.g., dry, hot, or windy climates) may cause or trigger lip inflammation. Emotional and psychological stress are also mentioned in the etiology of some lip inflammations (e.g., exfoliative cheilitis) and may be associated with nervous habits such as lip licking. To better manage cheilitis, it is also helpful to look for potential concomitant comorbidities and the presence of related diseases/conditions. Some forms of cheilitis accompany dermatologic or systemic diseases (lichen, pemphigus or pemphigoid, erythema multiforme, lupus, angioedema, xerostomia, etc.) that should be uncovered. Occasionally, lip lesions are persistent and involve histological changes: actinic cheilitis, granulomatous cheilitis, glandular cheilitis, and plasmacellular cheilitis. Perioral skin inflammation with simultaneous perioral dermatitis can have various causes: the use of corticosteroids and cosmetics, dysfunction of the skin’s epidermal barrier, a contact reaction to allergens or irritants (e.g., toothpaste, dental fillings), microorganisms (e.g., Demodex spp., Candida albicans, fusiform bacteria), hormonal changes, or an atopic predisposition. Epidermal barrier dysfunction can worsen perioral dermatitis lesions and can also be related to secondary vitamin or mineral deficiencies (e.g., zinc deficiency), occlusive emollient use, sunscreen use, or excessive exposure to environmental factors such as heat, wind, and ultraviolet light. Current trends in research are uncovering valuable information concerning the skin microbiome and disruption of the epidermal barrier of persons suffering from perioral dermatitis. Ultimately, an effective approach to patient management must take all these factors and new research into account.