Early studies suggested that the induction of an effective immune response could lead to elimination of residual tumour. Over a hundred years ago Coley invented his eponymous named "toxins" that appeared to induce a strong inflammatory response, leading to tumour reduction. Subsequent attempts to enhance the immune response have essentially been on a vaccine basis, trying to induce a specific response against the tumour. Numerous vaccine approaches have claimed to give significant clinical benefit in clinical response but very few of these have survived a randomised trial. A major reason for this is the heterogeneity of many tumours, as well as the various forms of defence against an immune response that they employ. It was thought that chemotherapy and radiotherapy were mutually exclusive for immunotherapy using the vaccine approach. More recently, however, it has become appreciated that vaccine approaches may enhance subsequent responses to radiotherapy and that certain chemotherapies actually enhance responses to vaccines. It has been suggested that one of the mechanisms of action of chemotherapy is to reduce the cells that suppress T-cells. These cells primarily defend the tumour from an immunological attack, but more recently it has been suggested that the benefit may encompass other aspects, such as enhancing antiangiogenic responses. One reason why immunostimulatory approaches may be so useful in cancer is that many cancers evolve out of a chronic inflammatory environment that actively suppresses cell mediated immune responses and enhances tumour angiogenesis. An ideal cancer drug would therefore be expected to have these properties. One such drug is lenalidomide, which features include marked immune stimulatory properties as well being able to inhibit regulatory T-cells. They have also been shown to enhance anticancer activity with vaccines in both preclinical models and more recently in clinical observations, where the responses to vaccines in patients with myeloma is much higher when they are on lenalidomide than other treatments. A number of regularly used chemotherapy regimens have marked activity in modulating the immune response. These maybe of benefit and the regimens will be reviewed, which include gemcitabine, cyclophosphamide and the IMiDs.