Medical imaging has evolved from a pure visualization tool to representing a primary source of analytic approaches towards in vivo disease characterization. Hybrid imaging is an integral part of this approach, as it provides complementary visual and quantitative information in the form of morphological and functional insights into the living body. As such, non-invasive imaging modalities no longer provide images only, but data, as stated recently by pioneers in the field. Today, such information, together with other, non-imaging medical data creates highly heterogeneous data sets that underpin the concept of medical big data. While the exponential growth of medical big data challenges their processing, they inherently contain information that benefits a patient-centric personalized healthcare. Novel machine learning approaches combined with high-performance distributed cloud computing technologies help explore medical big data. Such exploration and subsequent generation of knowledge require a profound understanding of the technical challenges. These challenges increase in complexity when employing hybrid, aka dual- or even multi-modality image data as input to big data repositories. This paper provides a general insight into medical big data analysis in light of the use of hybrid imaging information. First, hybrid imaging is introduced (see further contributions to this special Research Topic), also in the context of medical big data, then the technological background of machine learning as well as state-of-the-art distributed cloud computing technologies are presented, followed by the discussion of data preservation and data sharing trends. Joint data exploration endeavours in the context of in vivo radiomics and hybrid imaging will be presented. Standardization challenges of imaging protocol, delineation, feature engineering and machine learning evaluation will be detailed. Last, the paper will provide an outlook into the future role of hybrid imaging in view of personalized medicine, whereby a focus will be given to the derivation of prediction models as part of clinical decision support systems, to which machine learning approaches and hybrid imaging can be anchored.