This thesis addresses the problem of linking molecular status of glioblastoma patients with imaging-derived phenotypic traits. Glioblastoma (GBM) is the most common and aggressive type of malignant brain tumor, with a median survival of only 12-15 months. Due to GBM’s complex heterogeneity in gene expression, the responses to current treatment strategy varies considerably among different patients. There is an urgent need for a deeper understanding of tumor biology and alternative personalized therapeutic intervention. Magnetic Resonance Imaging (MRI) and histologic images are routinely used for GBM diagnosis. A natural question to ask is that if the phenotypic tumor traits from these images can be linked to tumor molecular signatures. In this thesis, we explore the imaging-genomic relationship in GBM via three approaches. The first approach aims to find texture features extracted from the MRI images that best discriminate GBM molecular subtypes. The second approach aims to find gene networks that determines the radiologically-defined tumor sub-compartment volumes. The third approach aims to quantify GBM histologic hallmarks and correlate them with biological pathway activities. Our study shows that linking imaging traits with tumor molecular status can lead to discoveries that have potential clinical relevance and provide biological insight.