Background It is a common practice that researchers collect a set of samples without discriminating the mutants and their wild-type counterparts to characterize the transcriptional, methylational and/or copy number changes of pre-defined candidate oncogenes or tumor suppressor genes (TSGs), although some examples are known that carcinogenic mutants may express and function completely differently from their wild-type counterparts. Principal Findings Based on various high-throughput data without mutation information for typical cancer types, we surprisingly found that about half of known oncogenes (or TSGs) pre-defined by mutations were down-regulated (or up-regulated) and hypermethylated (or hypomethylated) in their corresponding cancer types. Therefore, the overall expression and/or methylation changes of genes detected in a set of samples without discriminating the mutants and their wild-type counterparts cannot indicate the carcinogenic roles of the mutants. We also found that about half of known oncogenes were located in deletion regions, whereas all known TSGs were located in deletion regions. Thus, both oncogenes and TSGs may be located in deletion regions and thus deletions can indicate TSGs only if the gene is found to be deleted as a whole. In contrast, amplifications are restricted to oncogenes and thus can be used to support either the dysregulated wild-type gene or its mutant as an oncogene. Conclusions We demonstrated that using the transcriptional, methylational and/or copy number changes without mutation information to characterize oncogenes and TSGs, which is a currently still widely adopted strategy, will most often produce misleading results. Our analysis highlights the importance of evaluating expression, methylation and copy number changes together with gene mutation data in the same set of samples in order to determine the distinct roles of the mutants and their wild-type counterparts.