In the context of Predictive, Preventive and Personalized Medicine (PPPM), radiologists play an essential role in patient management throughout the different phases of hepatocellular carcinoma (HCC). This includes diagnosis, staging, treatment planning, and evaluation of response to treatment. This chapter provides an in-depth examination of the fundamental pathophysiologic mechanisms underlying the radiologic diagnosis and assessment of HCC. Observations made in contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), in conjunction with alpha-fetoprotein (AFP) can allow the diagnosis of HCC to be made with confidence without the need for biopsy, in many cases. Treatment decisions and prognosis are strongly influenced by the tumor extension, the number and size of lesions, tumor location, biliary dilatation, ascites, and the presence of macrovascular invasion and extrahepatic tumor spread. In addition, radiologic assessment of co-morbidities and response to previous treatments must be included in the overall assessment. The patient-specific findings from diagnostic imaging and interventional radiology identified in this chapter will be designated as Information Entities (IEs) in later chapters. These IEs will ultimately be used in the generation of Digital Patient Models (DPMs) to facilitate diagnosis, prognosis, and treatment selection, i.e. Model Guided Therapy (MGT) and PPPM.