Over the past 10 years our knowledge of cellular and molecular dynamics of teleost humoral immunity has increased enormously to now include: the existence of multiple isotypes, affinity-driven modulation of antibody structure and function, the unique trafficking patterns of each stage of B cell differentiation (including the plasma blast, short-lived and long-lived plasma cell, and the memory cell). Unfortunately the work which has generated the bulk of this information has generally employed defined antigens rather than vaccines. Thus, the focus of this review is to relate these aspects of immunity that are requisite for a mechanistic understanding of the generation of prophylactic immunity to the necessary analysis of responses to vaccines and vaccine candidates.