Abstract: CD8 T cells and natural killer (NK) cells play an important role in defense against viral infection and cancer. Both cell types use multiple cytotoxic pathways to kill infected or deranged host cells and can also directly target bacteria and parasites. In this talk I will discuss three stories related to how CD8 T cells and NK cells establish cytotoxic immunological synapses. The first story relates to effector mechanisms utilized by CD8 T cells and NK cells with supramolecular assemblies based on 100 nm particles. Tactical considerations may determine which cytotoxic mechanism is deployed. FAS on targets triggered extracellular vesicles with FasL, whereas 100 nm protein “bombs” with a core of perforin and granzymes and a shell of thrombospondin-1 were deployed when the target expressed ICAM1. We refer to these protein bombs as supramolecular attack particles or SMAPs. Adhesion molecules like ICAM1 and CD58 establish the immunological synapse. I will describe how CD2 contributes to signal amplification in synapses and how CD2 expression is low in “exhausted” tumor infiltrating lymphocytes in several types of cancer. Finally, I will discuss how malaria parasites use some members of a large family of proteins called RIFINs to inhibit attack by NK cells-shifting the activating immune synapse to an inhibitory immune synapse to protect parasitized red blood cells.