Targeted cancer therapies encompass an exponentially growing number of agents that involve a myriad of molecular pathways. To excel within this rapidly changing field of clinical oncology, radiologists must eschew traditional organ system-based approaches of cataloging adverse effects in favor of a conceptual framework that incorporates molecular mechanisms and associated clinical outcomes. Understanding molecular mechanisms that underlie imaging manifestations of adverse effects and known associations with treatment response allows radiologists to more effectively recognize adverse effects and differentiate them from tumor progression. Radiologists can therefore more effectively guide oncologists in the management of adverse effects and treatment decisions regarding continuation or cessation of drug therapy. Adverse effects from targeted cancer therapies can be classified into four categories: (a) category 1, on-target adverse effects associated with treatment response; (b) category 2, on-target adverse effects without associated treatment response; (c) category 3, off-target adverse effects; and (d) category 4, tumor necrosis-related adverse effects. This review focuses on adverse effects primarily within the abdomen and pelvis classified according to established or hypothesized molecular mechanisms and illustrated with images of classic examples and several potential emerging toxic effects.