The immune system has many important regulatory roles in cancer development and progression. Given the emergence of effective immune therapies against many cancers, reliable predictors of response are needed. One method of determining response is by evaluating immune cell populations from treated and untreated tumor samples. The amount of material obtained from tumor biopsies can be limited; therefore, gene-based or protein-based analyses may be attractive because they require minimal tissue. Cell-specific signatures are being analyzed with use of the latest technologies, including NanoString's nCounter technology, intracellular staining flow cytometry, cytometry by time-of-flight, RNA-Seq, and barcoding antibody-based protein arrays. These signatures provide information about the contributions of specific types of immune cells to bulk tumor samples. To date, both tumor tissue and immune cells have been analyzed for molecular expression profiles that can assess genes and proteins that are specific to immune cells, yielding results of varying specificity. Here, we discuss the importance of profiling tumor tissue and immune cells to identify immune-cell-associated genes and proteins and specific gene profiles of immune cells. We also discuss the use of these signatures in cancer treatment and the challenges faced in molecular expression profiling of immune cell populations.