Monoclonal antibodies (mAbs) are a proven effective therapeutic modality in human malignancy. Several mAbs are approved to targets critical in aberrant oncogenic signaling within tumors and their microenvironment. These targets include secreted ligands (e.g., VEGF and HGH), their receptors (e.g., HER2 and VEGFR2), cell surface counter receptors and their receptor-bound ligands (e.g., PD1 and PD1L, respectively). The ability to genetically engineer the structure and/or functions of mAbs has significantly improved their effectiveness. Furthermore, advances in gene expression profiling, proteomics, deep sequencing and deciphering of complex signaling networks have revealed novel therapeutic targets. We review target selection, approved indications and the rationale for mAb utilization in solid and hematologic malignancies. We also discuss novel mAbs in early- and late-phase clinical trials that are likely to change the natural history of disease and improve survival. The future challenge is to design mAb-based novel trial designs for diagnostics and therapeutics for human malignancies.