Caries is a biofilm-mediated noncommunicable disease fueled by dietary sugar, neglected oral hygiene, and reduced saliva flow. General diseases may influence the oral environment through its pathogenesis, medication, and/or the caring of the condition. Associations between caries and chronic diseases are mainly derived from case–control studies with various sample sizes and quality of matching. Few observational studies are available and the majority of all research is conducted in childhood and among older adults. There is an increased caries risk for subjects with obesity, severe asthma, poorly controlled type 1 diabetes mellitus, and congenital heart diseases. An elevated caries frequency has also been reported for children with neuropsychiatric disorders and cleft lip palate and long-term cancer survivors. Frail elderly with cognitive impairments constitute a growing age group in society with caries risk due to age- and medication-induced salivary reduction. However, a general disease may not always have a negative influence on dental health. Therefore, a regular individual caries risk assessment is of utmost importance for clinical decision-making and tailoring of recall intervals. There is good evidence that preventive measures based on fluoride, saliva stimulation, and sugar awareness can prevent, control, and even arrest caries lesions in medically compromised patients of all ages.