It is becoming increasingly evident that the old paradigm of disease pathogenesis where a given genotype would determine a phenotype and this would lead to a particular disease is no longer acceptable. Many novel components are now recognized to be involved in the predisposition, triggering, progression and outcome of chronic inflammatory diseases like inflammatory bowel disease (IBD). Accordingly, investigation of IBD must recognize this complexity and take all potential components into account, if a full understanding of disease pathophysiology is to be reached and truly effective therapies developed based on this new global understanding. Essential to this approach is the notion of functional integration. Groups of functionally related pathogenic components must be assembled and studied as 'omes' like, for instance, the genome and the microbiome; at the same time all relevant 'omes' must be functionally and meaningfully integrated into the 'interactome', while the 'epigenome' should be used to dissect and understand the connections underlying the interactome. This is an ideal but also realistic scenario for the immediate future, as some of the 'omes' are already being explored in greater depth and their interactions examined through investigation of gene-gene (GXG) and gene-environment (GXE) interactions. Current knowledge of GXG and GXE and their impact on IBD pathogenesis is the focus of this review.