Introduction: The ongoing development of genomic medicine and the use of molecular and imaging markers in personalized medicine (PM) has arguably challenged the field of health economic modeling (HEM). This study aims to provide detailed insights into the current status of HEM in PM, in order to identify if and how modeling methods are used to address the challenges described in literature. Areas covered: A review was performed on studies that simulate health economic outcomes for personalized clinical pathways. Decision tree modeling and Markov modeling were the most observed methods. Not all identified challenges were frequently found, challenges regarding companion diagnostics, diagnostic performance, and evidence gaps were most often found. However, the extent to which challenges were addressed varied considerably between studies. Expert commentary: Challenges for HEM in PM are not yet routinely addressed which may indicate that either (1) their impact is less severe than expected, (2) they are hard to address and therefore not managed appropriately, or (3) HEM in PM is still in an early stage. As evidence on the impact of these challenges is still lacking, we believe that more concrete examples are needed to illustrate the identified challenges and to demonstrate methods to handle them.