In recent years, human exposure to particulate materials, especially nanomaterials (NMs) has become more common and widespread. Nanomaterials are making their way into many aspects of our lives enabling the development of new types of materials for industrial and biomedical applications, leading to the possibility of increased exposure to nanoscale particles for both workers and consumers. Throughout their life cycle (e.g. production; use; disposal), NMs can be released into the environment, potentially causing harmful effects on natural ecosystems, with possible repercussions for both humans and animals health. It is critical to assess the effect of particulate material on short and long-term human health, and this requires a deep understanding of their interplay with the immune system. Immunological assessment of NMs is crucial for determining their safety, and efficacy, how they modulate the immune system, and to prevent undesirable immune reactions. However, assessing the immunomodulatory properties of NMs presents several challenges due to their unique properties that greatly influence their biological interactions and toxicity profile. In this chapter, we will review fundamental concepts about the immune system, how particles can trigger immune responses, as well as some challenges and emerging technologies for assessing the toxicity and immunomodulatory properties of NMs.