Recent clinical successes with antibodies have reinvigorated interest in the identification and validation of new antigens for antibody therapy, including cell surface proteins for targeting in oncology, the focus of this review. Target identification commonly involves the search for differences between tumor and non-tumor cell lines and/or tissue at the DNA, mRNA, protein or antibody reactivity levels. The next stage, target validation, utilizes antibodies to profile the expression of antigen in normal and tumor tissue and to verify that the antigen is selectively expressed on the surface of tumor cells. Supportive evidence for protein expression is often sought by mRNA profiling and, sometimes, analysis for genomic defects. Unfortunately, concordance between mRNA and protein levels has been found in only about approximately 20% of cases and therefore must be evaluated for individual targets of interest. Antigens judged suitable for antibody targeting are then advanced to the next stage, namely, in vitro and then in vivo screening of antibodies for anti-tumor activities. Subsequent optimization of an antibody clinical lead for therapy is a desirable, if not obligatory, step to developing an antibody as an anti-cancer therapeutic. No single approach or even combination of methods has emerged as the preferred way to identify surface antigens suitable for targeting in oncology. Major options at each step in the process are reviewed here, including their strengths and limitations.