Multimorbidity, defined as the coexistence of two or more chronic conditions, is increasingly prevalent in internal medicine, yet clinical practice guidelines (CPGs) remain largely disease-specific. This structural mismatch generates therapeutic conflicts, polypharmacy, and increased treatment burden. Evidence from recent systematic reviews highlights that patients with multimorbidity are frequently excluded from randomized trials, limiting guideline applicability, and that existing multimorbidity guidelines often lack methodological rigor, integration of patient preferences, and assessment of treatment burden. Translating siloed recommendations into clinical decision-support systems is further constrained by interoperability challenges, as exemplified by the CAREPATH study. Clinical conflicts are particularly evident in common comorbidity clusters, such as hypertension with diabetes mellitus and chronic kidney disease, where cumulative guideline application can increase adverse event risk and complexity of care. Additionally, heterogeneity in multimorbidity assessment-ranging from disease counts to severity-weighted indices-impedes consistent risk stratification and harmonized recommendations. To bridge these gaps, guideline reforms should include multimorbidity-specific pathways, incorporation of polypharmacy and treatment burden metrics, and structural formatting to support digital integration, without replacing disease-specific recommendations. Aligning guidelines with patient-centered, complexity-informed frameworks is essential to ensure safe, effective, and coherent care for the growing multimorbid population.