Some species of scuticociliates (Ciliophora) behave as facultative parasites and produce severe mortalities in cultured fish. Pathogenic scuticociliates can cause surface lesions and can also penetrate inside the body, where they feed on tissue and proliferate in the blood and most internal organs, killing the host in a few days. In this review, we describe the current knowledge on the protective role of fish cellular and humoral immune responses against these parasites. Immune humoral factors, especially complement, are of particular importance in defending fish against these ciliates. However, knowledge about how the fish immune system responds to scuticociliates is scant, and the cellular and molecular events that occur during the response are not known. We also describe the possible mechanisms used by scuticociliates to avoid or resist the defensive reaction of the host. For example, the release of proteases can help parasites enter fish tissues and impair the fish cellular and humoral responses. Several vaccine formulations containing scuticociliates have induced a good antibody response and protection in fish immunized and challenged with homologous strains of particular species. However, protection was not achieved in fish immunized and challenged with heterologous strains, and the antigens involved in protection and the antigenic differences between heterologous strains have not yet been determined.