Determinants of antipsychotic selection and response include parameters of the primary disorder, psychiatric and physical comorbidities, past treatment effects, patient preferences, availability and acceptability of different treatments and formulations, as well as expected efficacy and safety. In the absence of consistent and sufficiently large efficacy differences among antipsychotics (except for clozapine in refractory patients), and in view of a greater focus on physical health, functional outcomes and quality of life, relatively more predictable differences in adverse events have become an important management consideration. Treatments are often selected because of a relatively lower propensity for extrapyramidal and sexual side effects, sedation, and, especially, the reduced development of cardiometabolic risk states and disorders. In this context, differences in receptor binding affinity, intrinsic activity and in the half life of antipsychotics are crucial to adopt adequate dosing and switching strategies. Dopamine rebound phenomena can occur when the level of dopamine blockade is not kept relatively constant during the switch process. This can happen when the new antipsychotic is underdosed or not fully absorbed, the switch is too abrupt from an antipsychotic with a short half life to one with a much longer half life, or when a dopamine antagonist is switched too fast to an antipsychotic with markedly less dopamine affinity or to a partial dopamine agonist. Intra-switch destabilization can also occur when changing too quickly from antipsychotics with strong histaminergic and/or cholinergic blockade to ones with lower affinity to these receptors. Overlapping “plateau” switch strategies and transient co-treatment with calming medications, such as benzodiazepines, have emerged as potential solutions to these rebound phenomena that can complicate the early switch period. To optimize outcomes, antipsychotic treatment should be pharmacologically informed and measurement based, combining both acute and long-term management goals and balancing efficacy and adverse effect considerations.